Articles tagged as "Canada"

Excessive cardiovascular morbidity and mortality among people living with HIV – preventable with better services?

Editor’s notes: Opportunities to prevent mortality among people living with HIV also include careful attention to risk factors for modifiable cardiovascular health risk factors such as smoking, cholesterol levels, weight and exercise.  In an interesting study from Canada, Jeon and colleagues used the Ontario administrative databases to look at differences between 259 475 people being admitted with acute myocardial infarction according to their HIV status.  Overall, people living with HIV who had heart attacks were around 15 years younger and more than twice as likely to die within 30 days following discharge from the hospital compared to HIV-negative people.  This was not because people living with HIV had received care that was obviously different, with similar rates of revascularisation procedures and follow up visits to the cardiology services.  The study highlights the ongoing uncertainty about the reasons for increased morbidity and mortality among people living with HIV.  However, it is clear that we do have several well proven tools with which to reduce cardiovascular morbidity, so we should ensure that they are incorporated into HIV treatment services.

The relationship between known indicators of cardiovascular risk and HIV were also studied in 67 black South Africans living with HIV.  Borkum and colleagues demonstrate that HIV infection in black South Africans living with HIV was generally well controlled with 84% being virally suppressed and that they had a median CD4 count of over 500 cells per microlitre.  Nonetheless, most had a variety of characteristics that suggest that they were at high risk of cardiovascular events.  Markers of inflammation were raised in 68% and “non-dipping” blood pressure, which is a measure of excessive stiffness of the arteries, was present in 65%.  Straightforward measures that could be made even at the most peripheral ART clinic also demonstrated risk, with 67% being classified as overweight and 76% having an increased waist circumference, both well recognized independent risk factors for cardiovascular disease.  Worryingly this sample, which was largely female (91%), had an average age of only 42 years.  It is clear that intervention on cardiovascular risks is something for all ART providers to consider in every setting.

The Australian Positive and Peers Longevity Evaluation study (beautifully given the acronym of APPLES) also points out the importance of making valid comparisons between people living with HIV and their HIV negative peers.  In Australia, almost half of all people living with HIV are now over the age of 50 years.  Petoumenos and colleagues show that among gay and bisexual men older than 55 years, recruited in Sydney, those living with HIV were more likely to report noncommunicable comorbidities including heart disease and diabetes. However, some of the more obvious risk factors, such as smoking status, were not different between the groups and people living with HIV drank less alcohol than their HIV negative peers.  The relationships between HIV, lifestyle and noncommunicable disease risk are complex but probably important as the population of people living with HIV continues to age.

In a study from the Cohorte de la Red de Investigación en Sida (CoRIS) in Spain, Masiá and colleagues have also explored long term outcomes of almost 9000 people living with HIV and their experience of non-AIDS defining events.  They show that mortality rates are considerably higher in people living with HIV who have any non-AIDS event, even if these are traditionally considered less severe, such as bacterial pneumonia, psychiatric diseases, bone fractures, or diabetes. In addition to standard indicators (such as low CD4 count at ART initiation), we should take the development of non-AIDS events as a warning to intensify management efforts and more targeted prevention of complications.

In the UK, Molloy and colleagues conducted an audit of clinical services provided at different sites.  They show that systems need to catch up with the changes in life experience of people living with HIV.  While sexual health screening was almost universally available, only 71.4% of sites were able to offer cervical cytology despite the increased risk of cervical cancer in women living with HIV.  Less than half of people taking ART had their risk for cardiovascular disease documented.  Regular audit of appropriate services, even with simple checklists for service providers is a strong tool to improve care for people living with HIV and should have a direct impact on mortality.

 

Mortality and health service use following acute myocardial infarction among persons with HIV: a population-based study

 

Jeon C, Lau C, Kendall CE, Burchell AN, Bayoumi AM, Loutfy M, Rourke SB, Antoniou T. AIDS Res Hum Retroviruses. 2017 Sep 14. doi: 10.1089/AID.2017.0128. [Epub ahead of print]

People with HIV have higher rates of acute myocardial infarction (AMI) than HIV-negative individuals. We compared mortality risk and health service use following AMI among people with and without HIV between January 1, 2002, and March 31, 2015. We conducted a population-based study using Ontario's administrative databases. Our primary outcomes were risk of inpatient death and death at 30 days following hospital discharge. In secondary analyses, we compared use of revascularization procedures within 90 days of AMI, as well as readmission or emergency department visits for heart disease and cardiology follow-up within 90 days of discharge. We studied 259 475 AMI patients, of whom 345 (0.13%) were people with HIV. AMI patients with HIV were younger than HIV-negative patients (mean age ± standard deviation: 54.4 ± 10.5 years vs. 69.3 ± 14.3 years). Following multivariable adjustment, the odds ratios for inpatient death and death at 30 days following discharge were 1.04 [95% confidence intervals (CI) 0.64-1.56] and 2.42 (95% CI 1.00-4.92), respectively. In secondary analyses, no differences were observed in receipt of revascularization procedures (hazard ratio (HR) 0.98; 95% CI 0.85-1.12), readmission or emergency department visit for heart disease (HR 1.18; 95% CI 0.85-1.62), or cardiology follow-up (HR 0.88; 95% CI 0.76-1.01). People with HIV experience AMI at younger ages and may be at higher risk of death in the 30 days following hospital discharge, underscoring the importance of targeting modifiable cardiovascular disease risk factors in these patients.

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High prevalence of "non-dipping" blood pressure and vascular stiffness in HIV-infected South Africans on antiretrovirals

Borkum MS, Heckmann JM, Manning K, Dave JA, Levitt NS, Rayner BL, Wearne N. PLoS One. 2017 Sep 20;12(9):e0185003. doi: 10.1371/journal.pone.0185003. eCollection 2017.

Background: HIV-infected individuals are at increased risk of tissue inflammation and accelerated vascular aging ('inflamm-aging'). Abnormal diurnal blood pressure (BP) rhythms such as non-dipping may contribute to an increased risk of cardiovascular and cerebrovascular events in HIV infected individuals. However, little data exists on ambulatory blood pressure (ABP) and measures of vascular stiffness in the black African HIV infected population.

Methods: This is a cross-sectional analysis of otherwise well, HIV infected outpatients on ART for >5 years. Study assessments included: 24hr ABP monitoring, pulse wave velocity (PWV) and central aortic systolic pressure (CASP) using a AtCor Medical Sphygmocor device, fasting lipogram, oral glucose tolerance test, high-sensitivity C-reactive protein (hsCRP) and anthropometric data. Patients completed a questionnaire of autonomic symptoms. CD4+ counts and viral loads were obtained from the National Laboratory results system.

Results: Sixty-seven black participants were included in the analysis of whom 91% (n = 61) were female with a mean age of 42.2 ± 8.6 years. The median duration on ART was 7.5 years (IQR = 6-10), 84% were virally supressed and the median CD4 count was 529.5cells/mm3 (IQR = 372.0-686.5). The majority (67%) were classified as overweight and 76% had an increased waist circumference, yet only 88% of participants were normotensive. A hsCRP level in the high cardiovascular risk category was found in 68% of participants. The prevalence of non-dipping BP was 65%. Interestingly, there was no association on multivariable analysis between dipping status and traditional risk factors for non-dipping BP, such as: obesity, autonomic dysfunction and older age.

Conclusion: This relatively young cross-sectional sample of predominantly normotensive, but overweight black women on effective ART >5 years showed: a high prevalence of non-dipping BP, inflammation and vascular stiffness. Causality cannot be inferred but cardiovascular risk reduction should be emphasized in these patients.  

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Prevalence of self-reported comorbidities in HIV positive and HIV negative men who have sex with men over 55 years—The Australian Positive & Peers Longevity Evaluation Study (APPLES)

Petoumenos K, Huang R, Hoy J, Bloch M, Templeton DJ, Baker D, Giles M, Law MG, Cooper DA. PLoS One. 2017 Sep 8;12(9):e0184583. doi: 10.1371/journal.pone.0184583. eCollection 2017.

In Australia, almost half of HIV-positive people are now aged over 50 and are predominately gay and bisexual men (GBM). Compared to the general HIV-negative population, GBM engage more in behaviours that may increase the risk of age-related comorbidities, including smoking, high alcohol consumption and recreational drug use. The objective of APPLES was to compare comorbidities and risk factors in HIV-positive older GBM with an appropriate control group of HIV-negative GBM. We undertook a prospectively recruited cross-sectional sample of HIV-positive and HIV-negative GBM ≥ 55 years. Detailed data collection included clinic data, a health and lifestyle survey, and blood sample collection. We report key demographic, laboratory markers and self-reported comorbidities by HIV status. For selected comorbidities we also adjust HIV status a priori for age, smoking and body mass index. Over 16 months 228 HIV-positive and 218 HIV-negative men were recruited. Median age was 63 years (IQR: 59-67). Although more HIV-positive men reported having ever smoked, smoking status was not statistically different between HIV positive and HIV negative men (p = 0.081). Greater alcohol use was reported by HIV-negative men (p = 0.002), and recreational drug use reported more often by HIV-positive men (p<0.001). After adjustment, HIV-positive men had significantly increased odds of diabetes (adjusted Odds ratio (aOR): 1.97, p = 0.038), thrombosis (aOR: 3.08, p = 0.007), neuropathy (aOR: 34.6, P<0.001), and non-significantly increased odds for heart-disease (aOR: 1.71, p = 0.077). In conclusion, HIV-positive GBM have significantly increased odds for key self-reported comorbidities. This study underscores the importance of an appropriate HIV-negative control group for more accurate evaluation of the risk and attribution of age-related comorbidities in HIV-positive people.

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Prediction of long-term outcomes of HIV-infected patients developing non-AIDS events using a multistate approach

Masiá M, Padilla S, Moreno S, Barber X, Iribarren JA, Del Romero J, Gómez-Sirvent JL, Rivero M, Vidal F, Campins AA, Gutiérrez F; Cohorte de la Red de Investigación en Sida (CoRIS). PLoS One. 2017 Sep 8;12(9):e0184329. doi: 10.1371/journal.pone.0184329. eCollection 2017.

Objectives: Outcomes of people living with HIV (PLWH) developing non-AIDS events (NAEs) remain poorly defined. We aimed to classify NAEs according to severity, and to describe clinical outcomes and prognostic factors after NAE occurrence using data from CoRIS, a large Spanish HIV cohort from 2004 to 2013.

Design: Prospective multicenter cohort study.

Methods: Using a multistate approach we estimated 3 transition probabilities: from alive and NAE-free to alive and NAE-experienced ("NAE development"); from alive and NAE-experienced to death ("Death after NAE"); and from alive and NAE-free to death ("Death without NAE"). We analyzed the effect of different covariates, including demographic, immunologic and virologic data, on death or NAE development, based on estimates of hazard ratios (HR). We focused on the transition "Death after NAE".

Results: 8789 PLWH were followed-up until death, cohort censoring or loss to follow-up. 792 first incident NAEs occurred in 9.01% PLWH (incidence rate 28.76; 95% confidence interval [CI], 26.80-30.84, per 1000 patient-years). 112 (14.14%) NAE-experienced PLWH and 240 (2.73%) NAE-free PLWH died. Adjusted HR for the transition "Death after NAE" was 12.1 (95%CI, 4.90-29.89). There was a graded increase in the adjusted HRs for mortality according to NAE severity category: HR (95%CI), 4.02 (2.45-6.57) for intermediate-severity; and 9.85 (5.45-17.81) for serious NAEs compared to low-severity NAEs. Male sex (HR 2.04; 95% CI, 1.11-3.84), age >50 years (1.78, 1.08-2.94), hepatitis C-coinfection (2.52, 1.38-4.61), lower CD4 cell count at cohort entry (HR 2.49; 95%CI 1.20-5.14 for CD4 cell count below 200 and HR 2.16; 95%CI 1.01-4.66 for CD4 cell count between 200-350, both compared to CD4 cell count higher than 500) and concomitant CD4 <200 cells/mL (2.22, 1.42-3.44) were associated with death after NAE. CD4 count and HIV-1 RNA at engagement, previous AIDS and hepatitis C-coinfection predicted mortality in NAE-free persons.

Conclusion: NAEs, including low-severity events, increase prominently the risk for mortality in PLWH. Prognostic factors differ between NAE-experienced and NAE-free persons. These findings should be taken into account in the clinical management of PLWH developing NAEs and may permit more targeted prevention efforts.

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Routine monitoring and assessment of adults living with HIV: results of the British HIV Association (BHIVA) national audit 2015

Molloy A, Curtis H, Burns F, Freedman A; BHIVA Audit and Standards Sub-Committee. BMC Infect Dis. 2017 Sep 13;17(1):619. doi: 10.1186/s12879-017-2708-y.

Background: The clinical care of people living with HIV changed fundamentally as a result of the development of effective antiretroviral therapy (ART). HIV infection is now a long-term treatable condition. We report a national audit to assess adherence to British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals.

Methods: All UK sites known as providers of adult HIV outpatient services were invited to complete a case-note review and a brief survey of local clinic practices. Participating sites were asked to randomly select 50-100 adults, who attended for specialist HIV care during 2014 and/or 2015. Each site collected data electronically using a self-audit spreadsheet tool. This included demographic details (gender, ethnicity, HIV exposure, and age) and whether 22 standardised and pre-defined clinical audited outcomes had been recorded.

Results: Data were collected on 8258 adults from 123 sites, representing approximately 10% of people living with HIV reported in public health surveillance as attending UK HIV services. Sexual health screening was provided within 96.4% of HIV services, cervical cytology and influenza vaccination within 71.4% of HIV services. There was wide variation in resistance testing across sites. Only 44.9% of patients on ART had a documented 10-year CVD risk within the past three years and fracture risk had been assessed within the past three years for only 16.7% patients aged over 50 years.

Conclusions: There was high participation in the national audit and good practice was identified in some areas. However, improvements can be made in monitoring of cardiovascular risk, bone and sexual health.

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Africa, Europe, Northern America, Oceania
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Technology for tuberculosis, but why can’t we simply prevent it with proven tools that save lives?

Editor’s notes: Advances in diagnostic test technology have transformed the management of HIV and related infections.  For HIV, we have seen the introduction of self-administered test kits as well as new approaches to HIV viral load testing and nucleic acid based infant diagnosis.  Cryptococcal antigen screening can make prophylaxis and treatment more focused and potentially cost-effective.  For tuberculosis the biggest revolution has been the widespread introduction of the geneXpert® system.  The newest version, the Xpert® Ultra, is more sensitive than the original cartridge and is now being scaled up in countries including South Africa.  Agizew and colleagues conducted a study in Botswana to compare how the Xpert® MTB/RIF cartridge performed when used in centralized or peripheral health facilities.  Encouragingly there were few differences between the two levels, suggesting that the systems can be used close to the point of care.  However, the authors did note a surprisingly high level of unsuccessful tests (15%) both at the central lab and at the peripheral clinic.  Many of these test failures seem to have been because the sample was not processed correctly, and so should be amenable to better training for the health care workers performing the test.  The yield of testing varied greatly between the 13 sites. Between 1% and 23% of samples were positive for tuberculosis, with an average of 14%.  This may be because some sites were receiving specialized referrals.  Of the 447 positive samples, 8% were shown to be rifampicin resistant.  This figure is hard to interpret without more detail of the sample of patients in whom the test was performed.  Resistance is always higher among those who have been treated previously and may be higher in those referred to specialized centres.  Nonetheless, it demonstrates that there are a significant number of people with tuberculosis in Botswana who are very likely to have multi-drug resistant disease and need effective second line treatment.  Technology comes with a price tag.  In this study, the team bought test kits for $18 each, which makes it an expensive choice.  However, if it leads to prompt treatment of multi-drug resistant disease and more accurate diagnosis of tuberculosis, including among those living with HIV, this might still be cost-effective.

A small implementation research study from a single provincial referral centre in Zambia also examined the use and results of geneXpert® screening.  Masenga and colleagues found that 6.6% of 2374 samples tested by geneXpert® over the course of a year were positive for tuberculosis.  An additional 1301 samples were tested by sputum microscopy.  Their results suggest that geneXpert® was used mainly on people who were living with HIV, given that more than 90% of the positive samples came from people living with HIV.  5.9% of the 152 positive samples that were tested in the system were resistant to rifampicin, with no difference by gender.  This study leaves many questions unanswered, such as the sampling strategy, the history of previous treatment and the outcomes of the diagnosis in terms of treatment regimen and success.  However, it shines a light on the ways that new technology is now routine in some settings.  We need more research from diverse settings to paint the full picture of implementation outside traditional research centres.

Zenner and colleagues revisit the question of the risks and benefits of treatment for latent tuberculosis infection.  In a systematic review and network meta-analysis, they demonstrate once more that we have several effective ways to prevent tuberculosis among people living with HIV and that the harms are much smaller than the risks.  The question remains why we have failed so badly to scale up preventive therapy for tuberculosis alongside the success in scale up of antiretrovirals.

 

Peripheral clinic versus centralized laboratory-based XPERT® MTB/RIF performance: experience gained from a pragmatic, stepped-wedge trial in Botswana

Agizew T, Boyd R, Ndwapi N, Auld A, Basotli J, Nyirenda S, Tedla Z, Mathoma A, Mathebula U, Lesedi C, Pals S, Date A, Alexander H, Kuebrich T, Finlay A. PLoS One. 2017 Aug 17;12(8):e0183237. doi: 10.1371/journal.pone.0183237. eCollection 2017.

Background: In 2011, the Botswana National Tuberculosis Program adopted World Health Organization guidelines and introduced Xpert® MTB/RIF (Xpert®) assay to support intensified case finding among people living with HIV enrolling in care. An evaluation was designed to assess performance under operational conditions to inform the national Xpert® scale-up.

Methods: Xpert® was implemented from August 2012 through November 2014 with 13 GeneXpert® instruments (GeneXpert®) deployed in a phased approach over nine months: nine centralized laboratory and four point-of-care (POC) peripheral clinics. Clinicians and laboratorians were trained on the four-symptom tuberculosis screening algorithm and Xpert® testing. We documented our experience with staff training and GeneXpert® performance. Test results were extracted from GeneXpert® software; unsuccessful tests were analysed in relation to testing sites and trends over time.

Results: During 276 instrument-months of operation a total of 3630 tests were performed, of which 3102 (85%) were successful with interpretable results. Mycobacterium tuberculosis complex was detected for 447 (14%); of these, 36 (8%) were rifampicin resistant. Of all 3630 Xpert® tests, 528 (15%) were unsuccessful; of these 361 (68%) were classified as "error", 119 (23%) as "invalid" and 48 (9%) as "no result". The total number of recorded error codes was 385 and the most common reasons were related to sample processing (211; 55%) followed by power supply (77; 20%) and cartridge/module related (54; 14%). Cumulative incidence of unsuccessful test was similar between POC (17%, 95% CI: 11-25%) and centralized laboratory-based GeneXpert® instruments (14%, 95% CI: 11-17%; p = 0.140).

Conclusions: Xpert® introduction was successful in the Botswana setting. The incidence of unsuccessful test was similar by GeneXpert® location (POC vs. centralized laboratory). However, unsuccessful test incidence (15%) in our settings was higher than previously reported and was mostly related to improper sample processing. Ensuring adequate training among Xpert® testing staff is essential to minimize errors.

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Rifampicin resistance in mycobacterium tuberculosis patients using GeneXpert® at Livingstone Central Hospital for the year 2015: a cross sectional explorative study

Masenga SK, Mubila H, Hamooya BM. BMC Infect Dis. 2017 Sep 22;17(1):640. doi: 10.1186/s12879-017-2750-9

Background: Since the recent introduction of GeneXpert® for the detection of Tuberculosis (TB) drug resistance mutations in both primary resistance and acquired resistance in Zambia, little has been documented in literature on the issue of rifampicin resistance especially in the face of a high National TB burden. The study aimed to determine the prevalence of rifampicin resistance in tuberculosis patients at Livingstone Central Hospital for the year 2015.

Methods: This was a cross sectional study conducted at Livingstone Central Hospital where we reviewed 152 records (from January 1, 2015 to 31st December 2015) involving patients who presented with clinically suspected TB or documented TB, whose samples were sent to the laboratory for GeneXpert® Mycobacterium tuberculosis/rifampicin testing. Statistical evaluations used a one-sample test of proportion and Fisher's exact test.

Results: The age of participants ranged from 8 months to 73 years old (median = 34). Of the participants with complete data on gender, 99 (66%) and 52 (34%) were males and females respectively. The TB co-infection with HIV prevalence was 98.3% (p < 0.001). Prevalence of rifampicin resistance was 5.9% and there was no statistical significant difference between being male or female (p = 0.721).

Conclusion: We were able to show from our study, evidence of rifampicin resistance at Livingstone Central Hospital. Hence, there was need for further in-depth research and appropriate interventions (i.e. close follow-up and patient care for drug resistance positive patients).

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Treatment of latent tuberculosis infection: an updated network meta-analysis

Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ.  Ann Intern Med. 2017 Aug 15;167(4):248-255. doi: 10.7326/M17-0609. Epub 2017 Aug 1.

Background: Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI.

Purpose: To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children.

Data sources: PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied.

Study selection: Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB).

Data extraction: 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol.

Data synthesis: The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy.

Limitation: Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies.

Conclusion: Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin.

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Cryptoccal meningitis – the unacceptable consequence of leaving people behind during ART scale up

Editor’s notes: Cryptococcal meningitis is a severe disease that occurs in people with advanced immune suppression.  Its occurrence is an indicator that an HIV treatment programme is not working well, as it is rare in people whose CD4 count is above 100 cells per microlitre.  Rajasingham and colleagues have tried to estimate the current burden of disease.  This is not straightforward, as the number and proportion of people with advanced HIV disease is changing with the increasing scale up of antiretroviral therapy and earlier HIV diagnosis.  Nonetheless, severe immune suppression still occurs in those whose HIV infection remains undiagnosed or is diagnosed too late; among those who are not started on effective ARVs promptly and among those in whom ART fails and who are not managed effectively by the ART treatment programme.  The authors estimate that there could be more than 180 000 deaths from cryptococcal meningitis with the large majority (136 000) in Africa.  This makes Cryptococcus responsible for more than 15% of HIV-related deaths, second only to tuberculosis as a documented cause.  The authors emphasize the need for earlier diagnosis of HIV and better linkage to quality care programmes.  In the meantime, there are also advances in the screening, prophylaxis and treatment of Cryptococcus itself, which require investment in laboratory services and affordable medicines that can save lives until the effects of good ART improves the immune status.

Cassim and colleagues have developed a novel approach to costing different approaches to the roll out of technology for screening for cryptococcal antigen in the blood of people with advanced HIV infection.  Depending on the numbers of samples to be tested in the laboratory, a mix of single use lateral flow assays and automated enzyme immunoassays makes most sense.  The aim is to allow the more cost-effective high-volume sites to subsidize the low volume sites in order to ensure that as many people living with advanced HIV infection as possible can be screened.

Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis

Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, Denning DW, Loyse A, Boulware DR. Lancet Infect Dis. 2017 Aug;17(8):873-881. doi: 10.1016/S1473-3099(17)30243-8. Epub 2017 May 5.

Background: Cryptococcus is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. Global burden estimates are crucial to guide prevention strategies and to determine treatment needs, and we aimed to provide an updated estimate of global incidence of HIV-associated cryptococcal disease.

Methods: We used 2014 Joint UN Programme on HIV and AIDS estimates of adults (aged >15 years) with HIV and antiretroviral therapy (ART) coverage. Estimates of CD4 less than 100 cells per μL, virological failure incidence, and loss to follow-up were from published multinational cohorts in low-income and middle-income countries. We calculated those at risk for cryptococcal infection, specifically those with CD4 less than 100 cells/μL not on ART, and those with CD4 less than 100 cells per μL on ART but lost to follow-up or with virological failure. Cryptococcal antigenaemia prevalence by country was derived from 46 studies globally. Based on cryptococcal antigenaemia prevalence in each country and region, we estimated the annual numbers of people who are developing and dying from cryptococcal meningitis.

Findings: We estimated an average global cryptococcal antigenaemia prevalence of 6·0% (95% CI 5·8-6·2) among people with a CD4 cell count of less than 100 cells per μL, with 278 000 (95% CI 195 500-340 600) people positive for cryptococcal antigen globally and 223 100 (95% CI 150 600-282 400) incident cases of cryptococcal meningitis globally in 2014. Sub-Saharan Africa accounted for 73% of the estimated cryptococcal meningitis cases in 2014 (162 500 cases [95% CI 113 600-193 900]). Annual global deaths from cryptococcal meningitis were estimated at 181 100 (95% CI 119 400-234 300), with 135 900 (75%; [95% CI 93 900-163 900]) deaths in sub-Saharan Africa. Globally, cryptococcal meningitis was responsible for 15% of AIDS-related deaths (95% CI 10-19).

Interpretation: Our analysis highlights the substantial ongoing burden of HIV-associated cryptococcal disease, primarily in sub-Saharan Africa. Cryptococcal meningitis is a metric of HIV treatment programme failure; timely HIV testing and rapid linkage to care remain an urgent priority.

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Estimating the cost-per-result of a national reflexed cryptococcal antigenaemia screening program: Forecasting the impact of potential HIV guideline changes and treatment goals

Cassim N, Coetzee LM, Schnippel K, Glencross DK. PLoS One. 2017 Aug 22;12(8):e0182154. doi: 10.1371/journal.pone.0182154. eCollection 2017.

Introduction: During 2016, the National Health Laboratory Service (NHLS) introduced laboratory-based reflexed Cryptococcal antigen (CrAg) screening to detect early Cryptococcal disease in immunosuppressed HIV+ patients with a confirmed CD4 count of 100 cells/μl or less.

Objective: The aim of this study was to assess cost-per-result of a national screening program across different tiers of laboratory service, with variable daily CrAg test volumes. The impact of potential ART treatment guideline and treatment target changes on CrAg volumes, platform choice and laboratory workflow are considered.

Methods: CD4 data (with counts ≤ 100 cells/μl) from the fiscal year 2015/16 were extracted from the NHLS Corporate Date Warehouse and used to project anticipated daily CrAg testing volumes with appropriately-matched CrAg testing platforms allocated at each of 52 NHLS CD4 laboratories. A cost-per-result was calculated for four scenarios, including the existing service status quo (Scenario-I), and three other settings (as Scenarios II-IV) which were based on information from recent antiretroviral (ART) guidelines, District Health Information System (DHIS) data and UNAIDS 90/90/90 HIV/AIDS treatment targets. Scenario-II forecast CD4 testing offered only to new ART initiates recorded at DHIS. Scenario-III projected all patients notified as HIV+, but not yet on ART (recorded at DHIS) and Scenario-IV forecast CrAg screening in 90% of estimated HIV+ patients across South Africa (also DHIS). Stata was used to assess daily CrAg volumes at the 5th, 10th, 25th, 50th, 75th, 90th and 95th percentiles across 52 CD4-laboratories. Daily volumes were used to determine technical effort/ operator staff costs (% full time equivalent) and cost-per-result for all scenarios.

Results: Daily volumes ranged between 3 and 64 samples for Scenario-I at the 5th and 95th percentile. Similarly, daily volumes ranges of 1-12, 2-45 and 5-100 CrAg-directed samples were noted for Scenario's II, III and IV respectively. A cut-off of 30 CrAg tests per day defined use of either LFA or EIA platform. LFA cost-per-result ranged from $8.24 to $5.44 and EIA cost-per-result between $5.58 and $4.88 across the range of test volumes. The technical effort across scenarios ranged from 3.2-27.6% depending on test volumes and platform used.

Conclusion: The study reported the impact of programmatic testing requirements on varying CrAg test volumes that subsequently influenced choice of testing platform, laboratory workflow and cost-per-result. A novel percentiles approach is described that enables an overview of the cost-per-result across a national program. This approach facilitates cross-subsidisation of more expensive lower volume sites with cost-efficient, more centralized higher volume laboratories, mitigating against the risk of costing tests at a single site.

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Women know what they want, but need more reproductive health choices

Editor’s notes: Eliminating new HIV infections among children is often seen as a useful barometer of the overall success of the health systems as it relates to HIV.  Combination prevention approaches that include structural, behavioural and biomedical elements reduce the chance of women becoming HIV-positive.  Effective provision of a range of choices of modern contraceptive technology allow women to choose whether and when to have babies.  The option B+ approach should ensure that all pregnant women living with HIV are offered lifelong ART, which minimises the chance of mother to child transmission of HIV infection.  Continuing ART treatment for life keeps the mother healthy and allows her to support the development of her infant.

New HIV infections in children have declined by 46% since 2010, but there were still an estimated 160 000 new infections in 2016.  We know that in many settings the health system barometer is still forecasting plenty of clouds among the bright spells.  This month saw a range of papers describing reproductive health choices and HIV, as well as reflections on how option B+ is working, now that it is standard of care.

Contraceptive choices for women at high risk of HIV or living with HIV are complicated.  WHO recently reclassified long-acting progestin injections, such as DMPA, for women at high risk of HIV infection as category 2 in the Medical Eligibility for Contraception guidance. Category 2 means that, although the method is generally safe to use, clinical judgment and careful follow up may be required.  While the evidence comes from meta-analyses of observational studies, with inherent limitations, there is a reliable association between new HIV infection and the use of injectable progestins.  The ongoing randomized ECHO trial will provide higher quality evidence of causality, but results will not be reported until 2019. 

Mayhew et al. found that women living with HIV attending clinics in Kenya, were quite clear about their fertility intentions.  Many did not want more children, although they acknowledged pressure from partners and others.  Stigma around breast-feeding, worries about money and about possible health consequences of pregnancy were all reasons to decide not to have further children. The large majority used various sorts of contraception, but despite this 40% of pregnancies during the study were unintended.  The authors felt that the advice given by the clinics was not adequate and that choice of contraceptive method was limited.  In particular reliable long-acting methods, both reversible and not, were rarely taken up by the younger women.  Overall 16% of women used long-acting methods, and no pregnancies occurred in this group.

Chanda et al. focused on female sex workers in Zambia and found similar results.  Almost half the women had had terminations of pregnancies, and 62% of pregnancies were not planned.  Interestingly the availability of condoms at their places of work reduced the chances of unwanted pregnancy.  Approximately 39% used injectable long-acting contraceptives and only 18% used dual protection with a barrier in addition to a non-barrier method.  Less than one-third of the women reported that condoms were available often or always at work, and 23% reported using no contraception.  Providing access to condoms for sex workers in the highest transmission areas of countries like Zambia seems such an obvious pre-requisite for HIV programmes that it is extraordinary that in 2017 we still do not manage to do so.

Finally on this theme, Salters et al. demonstrate that contraceptive choice for women living with HIV is not only a challenge in sub-Saharan Africa.  The authors followed women in the Canadian HIV Women's Sexual and Reproductive Health Cohort Study and showed that 61% of reported pregnancies were unintended. Women with unintended pregnancies tended to be younger, single and born in Canada compared to women with planned pregnancies.  To support the second prong of the strategy to eliminate HIV infections in children, we need to improve on the integration between services for sexual and reproductive health and rights and services for women living with HIV.

Once women living with HIV are pregnant, the focus shifts to the third and fourth prong – preventing transmission to the infant and keeping the mother and infant healthy.  Option B+ has transformed the approach in most antenatal clinics with high rates of coverage of HIV testing and most women receiving ART during pregnancy.  In the One Stop Clinic in Ifakara, Tanzania, Gamell et al. show that almost all pregnant women, who do not already know that they are living with HIV, are offered an HIV test and that 94% accept it.  Retesting late in pregnancy is not yet routine, and only 3% were re-tested, of whom one (2%) had seroconverted.  Since acute HIV infection has such an important impact on the risk of transmission, re-testing later in pregnancy is now routine in many countries.  Coverage is far from complete, so it is not always clear whether the high rates of seroconversion observed reflect a selection bias in choosing women who are at particularly high risk.  This is an important area for research if we are to continue to drive down the already low transmission rates.  Similarly the authors found that women who slipped through the net and presented in labour, were not always tested and did have a higher prevalence of infection - 5.2% vs. 3.1%. The other significant finding in Ifakara was that, as in many cohort studies, women were happy to take ART during pregnancy to protect their infants, but retention in care thereafter was much less impressive.  Of women newly diagnosed with HIV infection during pregnancy, 27% were lost to follow up at the time of the analysis.

Chadambuka et al. used qualitative methods to understand what impact the shift to option B+ has had in their study area in Zimbabwe.  Overall, the women interviewed were very positive about treatment.  They believed that it was good for their babies and also good for them, making them look healthy and thus avoiding stigma.  However, women pointed out that their male partners are not exposed to as much information at the clinic or in the community.  As a result, many men are less keen to be tested and sometimes not keen for their partners to be taking medicine despite appearing healthy.  As one woman put it: “Very few men are supportive. You have to be strong. The men base their judgment on how healthy you appear to be as you carry yourself around and he also compares to how healthy he feels and opts to delay testing. But delaying only brings further harm. So when those men tell you to stop taking your medication, you need to tell them that they can stop if they want to, whilst you continue with your treatment.”  Within the power dynamics of many relationships, such a forthright approach may not be easy for all women.  So we need continued attention on how to engage men in the process and how to empower women to act as agents of change within their communities.

 

Fertility intentions and contraceptive practices among clinic-users living with HIV in Kenya: a mixed methods study

Mayhew SH, Colombini M, Kimani JK, Tomlin K, Warren CE; Integra Initiative, Mutemwa R. BMC Public Health. 2017 Jul 5;17(1):626. doi: 10.1186/s12889-017-4514-2.

Background: Preventing unwanted pregnancies in Women Living with HIV (WLHIV) is a recognised HIV-prevention strategy. This study explores the fertility intentions and contraceptive practices of WLHIV using services in Kenya.

Methods: Two hundred forty women self-identifying as WLHIV who attended reproductive health services in Kenya were interviewed with a structured questionnaire in 2011; 48 were also interviewed in-depth. STATA SE/13.1, Nvivo 8 and thematic analysis were used.

Results: Seventy one percent participants did not want another child; this was associated with having at least two living children and being the bread-winnerFP use was high (92%) but so were unintended pregnancies (40%) while living with HIV. 56 women reported becoming pregnant "while using FP": all were using condoms or short-term methods. Only 16% participants used effective long-acting reversible contraceptives or permanent methods (LARC-PM). Being older than 25 years and separated, widowed or divorced were significant predictors of long-term method use. Qualitative data revealed strong motivation among WLHIV to plan or prevent pregnancies to avoid negative health consequences. Few participants received good information about contraceptive choices.

Conclusions: WLHIV need better access to FP advice and a wider range of contraceptives including LARC to enable informed choices that will protect their fertility intentions, ensure planned pregnancies and promote safe child-bearing.

Trial registration: Integra is a non-randomised pre-post intervention trial registered with Current Controlled Trials ID: NCT01694862.

Abstract  Full-text [free] access

 

Contraceptive use and unplanned pregnancy among female sex workers in Zambia

Chanda MM, Ortblad KF, Mwale M, Chongo S, Kanchele C, Kamungoma N, Barresi LG, Harling G, Bärnighausen T, Oldenburg CE. Contraception. 2017 Sep;96(3):196-202. doi: 10.1016/j.contraception.2017.07.003. Epub 2017 Jul 12.

Objectives: Access to reproductive healthcare, including contraceptive services, is an essential component of comprehensive healthcare for female sex workers (FSW). Here, we evaluated the prevalence of and factors associated with contraceptive use, unplanned pregnancy, and pregnancy termination among FSW in three transit towns in Zambia.

Study design: Data arose from the baseline quantitative survey from a randomized controlled trial of HIV self-testing among FSW. Eligible participants were 18 years of age or older, exchanged sex for money or goods at least once in the past month, and were HIV-uninfected or status unknown without recent HIV testing (<3 months). Logistic regression models were used to assess factors associated with contraceptive use and unplanned pregnancy.

Results: Of 946 women eligible for this analysis, 84.1% had been pregnant at least once, and among those 61.6% had an unplanned pregnancy, and 47.7% had a terminated pregnancyIncarceration was associated with decreased odds of dual contraception use (aOR=0.46, 95% CI 0.32-0.67) and increased odds of unplanned pregnancy (aOR=1.75, 95% CI 1.56-1.97). Condom availability at work was associated with increased odds of using condoms only for contraception (aOR=1.74, 95% CI 1.21-2.51) and decreased odds of unplanned pregnancy (aOR=0.63, 95% CI 0.61-0.64).

Conclusions: FSW in this setting have large unmet reproductive health needs. Structural interventions, such as increasing condom availability in workplaces, may be useful for reducing the burden of unplanned pregnancy.

Abstract  Full-text [free] access

 

Pregnancy incidence and intention after HIV diagnosis among women living with HIV in Canada

Salters K, Loutfy M, de Pokomandy A, Money D, Pick N, Wang L, Jabbari S, Carter A, Webster K, Conway T, Dubuc D, O'Brien N, Proulx-Boucher K, Kaida A; CHIWOS Research Team. PLoS One. 2017 Jul 20;12(7):e0180524. doi: 10.1371/journal.pone.0180524. eCollection 2017.

Background: Pregnancy incidence rates among women living with HIV (WLWH) have increased over time due to longer life expectancy, improved health status, and improved access to and HIV prevention benefits of combination antiretroviral therapy (cART). However, it is unclear whether intended or unintended pregnancies are contributing to observed increases.

Methods: We analyzed retrospective data from the Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS). Kaplan-Meier methods and GEE Poisson models were used to measure cumulative incidence and incidence rate of pregnancy after HIV diagnosis overall, and by pregnancy intention. We used multivariable logistic regression models to examine independent correlates of unintended pregnancy among the most recent/current pregnancy.

Results: Of 1165 WLWH included in this analysis, 278 (23.9%) women reported 492 pregnancies after HIV diagnosis, 60.8% of which were unintendedUnintended pregnancy incidence (24.6 per 1000 women-years (WYs); 95% CI: 21.0, 28.7) was higher than intended pregnancy incidence (16.6 per 1000 WYs; 95% CI: 13.8, 20.1) (Rate Ratio: 1.5, 95% CI: 1.2-1.8). Pregnancy incidence among WLWH who initiated cART before or during pregnancy (29.1 per 1000 WYs with 95% CI: 25.1, 33.8) was higher than among WLWH not on cART during pregnancy (11.9 per 1000 WYs; 95% CI: 9.5, 14.9) (Rate Ratio: 2.4, 95% CI: 2.0-3.0). Women with current or recent unintended pregnancy (vs. intended pregnancy) had higher adjusted odds of being single (AOR: 1.94; 95% CI: 1.10, 3.42), younger at time of conception (AOR: 0.95 per year increase, 95% CI: 0.90, 0.99), and being born in Canada (AOR: 2.76, 95% CI: 1.55, 4.92).

Conclusion: Nearly one-quarter of women reported pregnancy after HIV diagnosis, with 61% of all pregnancies reported as unintended. Integrated HIV and reproductive health care programming is required to better support WLWH to optimize pregnancy planning and outcomes and to prevent unintended pregnancy.

Abstract  Full-text [free] access

 

Prevention of mother-to-child transmission of HIV Option B+ cascade in rural Tanzania: the One Stop Clinic model

Gamell A, Luwanda LB, Kalinjuma AV, Samson L, Ntamatungiro AJ, Weisser M, Gingo W, Tanner M, Hatz C, Letang E, Battegay M; KIULARCO Study Group. PLoS One. 2017 Jul 12;12(7):e0181096. doi: 10.1371/journal.pone.0181096. eCollection 2017.

Background: Strategies to improve the uptake of Prevention of Mother-To-Child Transmission of HIV (PMTCT) are needed. We integrated HIV and maternal, newborn and child health services in a One Stop Clinic to improve the PMTCT cascade in a rural Tanzanian setting.

Methods: The One Stop Clinic of Ifakara offers integral care to HIV-infected pregnant women and their families at one single place and time. All pregnant women and HIV-exposed infants attended during the first year of Option B+ implementation (04/2014-03/2015) were includedPMTCT was assessed at the antenatal clinic (ANC), HIV care and labour ward, and compared with the pre-B+ period. We also characterised HIV-infected pregnant women and evaluated the MTCT rate.

Results: 1579 women attended the ANC. Seven (0.4%) were known to be HIV-infectedOf the remainder, 98.5% (1548/1572) were offered an HIV test94% (1456/1548) accepted and 38 (2.6%) tested HIV-positive51 were re-screened for HIV during late pregnancy and one had seroconvertedThe HIV prevalence at the ANC was 3.1% (46/1463). Of the 39 newly diagnosed women, 35 (90%) were linked to care. HIV test was offered to >98% of ANC clients during both the pre- and post-B+ periods. During the post-B+ period, test acceptance (94% versus 90.5%, p<0.0001) and linkage to care (90% versus 26%, p<0.0001) increasedTen additional women diagnosed outside the ANC were linked to care. 82% (37/45) of these newly-enrolled women started antiretroviral treatment (ART). After a median time of 17 months, 27% (12/45) were lost to follow-up. 79 women under HIV care became pregnant and all received ART. After a median follow-up time of 19 months, 6% (5/79) had been lost. 5727 women delivered at the hospital, 20% (1155/5727) had unknown HIV serostatus. Of these, 30% (345/1155) were tested for HIV, and 18/345 (5.2%) were HIV-positive. Compared to the pre-B+ period more women were tested during labour (30% versus 2.4%, p<0.0001). During the study, the MTCT rate was 2.2%.

Conclusions: The implementation of Option B+ through an integrated service delivery model resulted in universal HIV testing in the ANC, high rates of linkage to care, and MTCT below the elimination threshold. However, HIV testing in late pregnancy and labour, and retention during early ART need to be improved.

Abstract  Full-text [free] access

 

Acceptability of lifelong treatment among HIV-positive pregnant and breastfeeding women (Option B+) in selected health facilities in Zimbabwe: a qualitative study

Chadambuka A, Katirayi L, Muchedzi A, Tumbare E, Musarandega R, Mahomva AI, Woelk G BMC Public Health. 2017 Jul 25;18(1):57. doi: 10.1186/s12889-017-4611-2.

Background: Zimbabwe's Ministry of Health and Child Care (MOHCC) adopted 2013 World Health Organization (WHO) prevention of mother-to-child HIV transmission (PMTCT) guidelines recommending initiation of HIV-positive pregnant and breastfeeding women (PPBW) on lifelong antiretroviral treatment (ART) irrespective of clinical stage (Option B+). Option B+ was officially launched in Zimbabwe in November 2013; however the acceptability of life-long ART and its potential uptake among women was not known.

Methods: A qualitative study was conducted at selected sites in Harare (urban) and Zvimba (rural) to explore Option B+ acceptability; barriers, and facilitators to ART adherence and service uptake. In-depth interviews (IDIs), focus group discussions (FGDs) and key informant interviews (KIIs) were conducted with PPBW, healthcare providers, and community members. All interviews were audio-recorded, transcribed, and translated; data were coded and analyzed in MaxQDA v10.

Results: Forty-three IDIs, 22 FGDs, and five KIIs were conducted. The majority of women accepted lifelong ART. There was however, a fear of commitment to taking lifelong medication because they were afraid of defaulting, especially after cessation of breastfeeding. There was confusion around dosage; and fear of side effects, not having enough food to take drugs, and the lack of opportunities to ask questions in counseling. Participants reported the need for strengthening community sensitization for Option B+. Facilitators included receiving a simplified pill regimen; ability to continue breastfeeding beyond 6 months like HIV-negative women; and partner, community and health worker support. Barriers included distance of health facility, non-disclosure of HIV status, poor male partner support and knowing someone who had negative experience on ART.

Conclusions: This study found that Option B+ is generally accepted among PPBW as a means to strengthen their health and protect their babies. Consistent with previous literature, this study demonstrated the importance of male partner and community support in satisfactory adherence to ART and enhancing counseling techniques. Strengthening community sensitization and male knowledge is critical to encourage women to disclose their HIV status and ensure successful adherence to ART. Targeting and engaging partners of women will remain key determinants to women's acceptance and adherence on ART under Option B+

Abstract  Full-text [free] access

Africa, Northern America
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90-90-90: a clear roadmap for HIV treatment. But each 90 brings with it opportunities and challenges

Editor’s notes: The discovery of effective antiretroviral therapy (ART) will go down in history as the greatest success of biomedical science of the past decades.  Landmark studies have shown that the earlier people living with HIV start ART, not only is their clinical outlook improved, but also their likelihood of transmitting infection to their sexual partners falls dramatically.  People who take their ART effectively and in whom the virus is suppressed to undetectable levels are no longer infectious.  A massive public health and social justice response has led to unprecedented scale up of this miraculous treatment.  There is widespread adoption of the UNAIDS 90-90-90 treatment target.  The target is easy to recite: 90% of people living with HIV know their status; 90% of people who know their status are on ART and 90% of people taking ART have suppressed their viral load.  Many mathematical models show that if these targets are achieved, there should be a substantial impact on the trajectory of the epidemic with a large reduction in new HIV infections and HIV-related deaths, leading to huge cost-savings in the future.

Several large community based studies have been established to examine both the necessary processes to reach these goals and the impact at community level of the wider coverage with effective ART.  We have commented in previous editions on the ANRS Treatment as Prevention (TasP) study in rural Kwazulu-Natal and on papers from the SEARCH study in rural Kenya and Uganda.  Not surprisingly, given the different contexts, approaches, methods and definitions, the studies each shed light on different aspects of the 90-90-90 target.

This month, there are two new papers from the PopART (HPTN071) study, along with an accompanying commentary from the TasP study team.  PopART is the largest of the large community randomized studies of the universal test and treat approach, nested within a broader combination prevention package.  The population covered by the trial is around one million people living in largely urban or peri-urban communities in Zambia and the Western Cape province of South Africa.  The approach used in two of the three arms of the trial, is to deliver HIV testing and other prevention services by means of community health workers.  These so called CHiPs (Community HIV care Providers) also encourage linkage of people either known to be or newly found to be living with HIV to the local government health facilities, where ART is started regardless of CD4 count in one arm of the study, or in line with government guidelines (which is now also regardless of CD4 count in both countries) in the other. In the third arm of the trial, there are no CHiPs and HIV testing and linkage to treatment is performed by routine services, with treatment also offered to all, regardless of CD4 count.

The papers in this month’s edition cover only the four Zambian communities receiving the most intensive package during the first year of the intervention. Shanaube and colleagues focus on the first 90, while Hayes and colleagues focus on the second 90.  The overall conclusion is that the CHiPs approach leads to a very high uptake of HIV testing, but that linkage to care still takes longer than expected.  However, there is a wealth of detail in both the process and the ways to measure these apparently straightforward statistics.  When the CHiPs actually see people, acceptance of HIV testing is very high, unless people have recently had an HIV test.  Even then, almost three quarters of women are happy to have another test four to six months after their most recent negative test, whereas for men, there is somewhat more reluctance.  The main challenges for the CHiPs are that people may need more than one visit to decide to test and that men are often not at home, despite multiple visits and scheduled appointments.  Furthermore, as Iwuju and Newell point out in their slightly pessimistic commentary, people move around and migration makes it hard to define a reliable denominator (a challenge also faced by the SEARCH team in Uganda and Kenya).  Around 20% of the people who knew they were HIV positive were not able to be seen at one year follow-up, so it is not possible to know whether they were linked to care or not.  The TasP study also found that the second 90 was the real challenges, with a very high coverage of HIV testing, but not enough linkage to lead to a reduction in incidence at the community level.

The PopART study is ongoing, and recent presentations suggest that with time, a larger proportion of people are indeed linking to care.  The lesson may be that it requires ongoing and continuing support in an urban and peri-urban community to achieve high levels of coverage.  We await eagerly the next instalments and final results demonstrating whether there is a wider public health impact which will not be available before 2019!

These huge longitudinal studies also remind us that the 90-90-90 target is defined as cross-sectional measurements, and does not take into account directly the length of time that it takes to start treatment or to become virally supressed.  The information from large cross-sectional studies, such as ICAP and PEPFAR’s population-based HIV impact assessments (PHIA) give a direct measurement of 90-90-90.  However, in contrast to PopART and the other community-based studies, gives no insight into the dynamics of the processes through which people decide to get tested, link to care and remain in care.

McCreesh and colleagues used an individual-based mathematical model of the flow through testing, linkage to treatment and retention based on data from Uganda and using a novel method of calibration.  They show that removing the CD4 threshold (as is recommended by WHO and the UNAIDS 90-90-90 target) is very likely to be the most cost-effective approach to reduce the burden of HIV over the years up to 2030.  However, they also found that their model predicts that efforts to improve linkage to and retention in care are likely to be more cost-effective than increased coverage of testing in Uganda.  This is in part because many Ugandans already know their HIV status as a result of previous efforts, so it should not be taken as a general recommendation not to work to improve the first 90 as well as the second two!  The authors state clear conclusions: “Our results strongly suggest that an increase in the rates of HIV testing in the general population in Uganda ….. should not be prioritized above interventions to improve linkage to, and retention in, care…..  In Uganda, interventions to improve retention in and movement through the HIV care pathway should be prioritized over case finding interventions in the general population.”

In rural Kwazulu-Natal, the challenge of retention among populations that are by necessity mobile was also shown in a study by Arnesen and colleagues.  In this study of risk factors for people on ART being lost to follow up they found that more than one quarter of the 3242 people on the treatment register in 15 primary care clinics were thought to be lost.  However, the authors found that one-third of these people labelled as lost were in fact taking treatment at another clinic.  As in other similar studies men were more likely to discontinue treatment, as were people with advanced immunosuppression (who are at high risk of dying in the absence of treatment) and being on ART for less than six months. This is a useful reminder of priorities.  Providing more support to men, and the sickest patients, maintaining closer supervision for the first year, might lead to better programme outcomes and (as predicted by the Ugandan model) save money in the medium term.

By comparison, a large records-based study in the United States of America by Youn and colleagues examined time trends in retention on treatment (persistence in the authors’ terminology).  The author used insurance claims for prescriptions for ART and for other medicines for heart disease, hypertension or diabetes taken regularly over a long time by both HIV positive and HIV-negative people.  They were able to examine persistence in over 40 000 people living with HIV starting treatment in 2001-2003 (when ART was more cumbersome and more toxic) compared to 2004-2006 and 2007-2010.  Persistence improved dramatically over this time period for ART, but hardly changed at all for the other medicines studied.  This demonstrates that the changes were not merely secular trends in the likelihood of remaining on treatment.  Interestingly, in people living with HIV, persistence on the non-HIV related medicines also improved, suggesting that HIV care provided additional benefits in terms of retention and adherence to medicines that went beyond ART. 

There was also good news from Australia, where Medland and colleagues used records from the two largest HIV treatment clinics in the state of Victoria to examine time trends in the delay from HIV diagnosis to starting ART.  Among 729 people started on ART, the proportion of patient in care and on ART within one year of diagnosis increased from 43.4% to 78.9% from 2011 to 2014.  By 2014, 50% of people were starting ART within 77 days of being diagnosed.  The authors point out that this is a key measurement of programme effectiveness that is not routinely captured.  Nor does it form part of the 90-90-90 targets.  Of course, it is important to remember that the period prior to HIV diagnosis is probably even more important in terms of risks of transmission, as there have been numerous studies showing that people who know their HIV status are less likely to transmit HIV.  So we really need to know the period from infection to HIV diagnosis, as well as the time from diagnosis to treatment, and perhaps also the time to become virally supressed.  Viral suppression can take months or even more than a year depending on an individual’s initial virological and immunological state and variations in response to treatment as well as with the choice of ART regimen.

Despite massive scale up of ART, there are still many people living with HIV who present to services late with a CD4 count of <200 cells per ml.  A recent report in MMWR, showed that in 10 PEPFAR supported countries, there are still as many as one third of people presenting late.  Many of these people have opportunistic infections that have characterised HIV infection since the earliest days of the AIDS epidemic.  Botswana has made huge progress towards 90-90-90, but Tenforde and colleagues show that cryptococcal meningitis is still a major health problem.  They were able to collect laboratory based data over the past decade, as well as more detailed records from the two largest referral centres.  Although the number of cases of cryptococcal meningitis has halved since 2004, when the scale up of ART in Botswana really got going, the two referral hospitals still see more than 150 cases per year.  Mortality is still horribly high.  Overall, the authors explored data from more than 5000 episodes of cryptococcal meningitis in 4702 individuals over the period 2004-2014.  For people who could be linked to their clinical medical records, they demonstrate that the risk rises dramatically as the CD4 count falls – people with a CD4 count of < 50 cells per ml have an incidence of around 2000/100 000 person years, whereas the rates of people with 50-100 or 100-200 cells per ml are around 350 and 80 respectively.  More than 90% of the cases identified occurred in people whose CD4 cell count was <200 cells per ml.  As other studies might have predicted, men are more affected, as they tend to present to services later.  The most useful medicines for cryptococcal meningitis, i.e., liposomal Amphotericin and 5 flucytosine, remain too expensive or not available in most African countries.  Not only do we need to bring the prices of these commodities down to affordable levels, but we also need continued efforts to engage men (and other populations who get left behind) earlier in the course of their HIV infection.

The improvements in overall survival and life expectancy for people living with HIV if they have access to effective treatments are well known.  A large collaborative study (the ART Cohort Collaboration) has brought together 18 European and North American cohorts in order to look at the mortality experienced in the first years after starting ART.  They found the biggest improvements in people who started treatment in the last period that they studied (2008-2010).  There were also greater changes in mortality in the second and third years after starting ART.  Even so, they conclude that life expectancy is still not as good as that of HIV negative people.  Previous studies have sometimes been biased towards people who survive longer, partly through not including as many people in the first year after ART when mortality is at its highest.  They propose that much of the improvement seen is due to newer drugs and more options for treatment failure.  They therefore caution against the temptation to save money on cheaper generics as they become available for older medicines that may be less palatable or less effective.

What works-reaching universal HIV testing: lessons from HPTN 071 (PopART) trial in Zambia

Shanaube K, Schaap A, Floyd S, Phiri M, Griffith S, Chaila J, Bock P, Hayes R, Fidler S, Ayles H; HPTN 071 (PopART) Study Team. AIDS. 2017 Jul 17;31(11):1555-1564. doi: 10.1097/QAD.0000000000001514..

Objective: To determine the uptake of home-based HIV counselling and testing (HCT) in four HPTN071 (PopART) trial communities (implementing a 'full' combination HIV prevention package that includes universal HIV testing and treatment) in Zambia. We also explore factors associated with uptake of HCT in these communities.

Design: HPTN071 (PopART) is a 3-arm community-randomized trial in 12 communities in Zambia and 9 communities in South Africa evaluating the impact of a combination HIV prevention package, including universal HIV testing and treatment, on HIV incidence.

Methods: Using a door-to-door approach that includes systematically re-visiting households, individuals were offered participation in the intervention and verbal consent was obtained. Data were analysed for the first 18 months of the intervention, December 2013 to June 2015 for individuals 18 years and older.

Results: Among 121 130 enumerated household members, 101 102 (83.5%) accepted the intervention. HCT uptake was 72.2% (66 894/92 612), similar by sex but varied across communities. HCT uptake was associated with younger age, sex, community, being symptomatic for TB and STI and longer time since previous HIV test. Knowledge of HIV status due to the intervention increased by 36% overall and by 66% among HIV positives; the highest impact was among 18-24 year olds.

Conclusion: Overall acceptance of HIV-testing through offering a door-to-door-based combination HIV prevention package was 72.2%. The intervention increased knowledge of HIV status from 50% to 90%. However, challenges still remain and a one-off intervention is unlikely to be successful but will require repeated visits and multiple strategies.

Abstract access

A universal testing and treatment intervention to improve HIV control: One-year results from intervention communities in Zambia in the HPTN 071 (PopART) cluster-randomised trial

Hayes R, Floyd S, Schaap A, Shanaube K, Bock P, Sabapathy K, Griffith S, Donnell D, Piwowar-Manning E, El-Sadr W, Beyers N, Ayles H, Fidler S; HPTN 071 (PopART) Study Team. PLoS Med. 2017 May 2;14(5):e1002292. doi: 10.1371/journal.pmed.1002292. eCollection 2017 May.

Objective: The Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets require that, by 2020, 90% of those living with HIV know their status, 90% of known HIV-positive individuals receive sustained antiretroviral therapy (ART), and 90% of individuals on ART have durable viral suppression. The HPTN 071 (PopART) trial is measuring the impact of a universal testing and treatment intervention on population-level HIV incidence in 21 urban communities in Zambia and South Africa. We report observational data from four communities in Zambia to assess progress towards the UNAIDS targets after 1 y of the PopART intervention.

Methods and Findings: The PopART intervention comprises annual rounds of home-based HIV testing delivered by community HIV-care providers (CHiPs) who also support linkage to care, ART retention, and other services. Data from four communities in Zambia receiving the full intervention (including immediate ART for all individuals with HIV) were used to determine proportions of participants who knew their HIV status after the CHiP visit; proportions linking to care and initiating ART following referral; and overall proportions of HIV-infected individuals who knew their status (first 90 target) and the proportion of these on ART (second 90 target), pre- and post-intervention. We are not able to assess progress towards the third 90 target at this stage of the study. Overall, 121 130 adults (59 283 men and 61 847 women) were enumerated in 46 714 households during the first annual round (December 2013 to June 2015). Of the 45 399 (77%) men and 55 703 (90%) women consenting to the intervention, 80% of men and 85% of women knew their HIV status after the CHiP visit. Of 6197 HIV-positive adults referred by CHiPs, 42% (95% CI: 40%-43%) initiated ART within 6 mo and 53% (95% CI: 52%-55%) within 12 mo. In the entire population, the estimated proportion of HIV-positive adults who knew their status increased from 52% to 78% for men and from 56% to 87% for women. The estimated proportion of known HIV-positive individuals on ART increased overall from 54% after the CHiP visit to 74% by the end of the round for men and from 53% to 73% for women. The estimated overall proportion of HIV-positive adults on ART, irrespective of whether they knew their status, increased from 44% to 61%, compared with the 81% target (the product of the first two 90 targets). Coverage was lower among young men and women than in older age groups. The main limitation of the study was the need for assumptions concerning knowledge of HIV status and ART coverage among adults not consenting to the intervention or HIV testing, although our conclusions were robust in sensitivity analyses.

Conclusions: In this analysis, acceptance of HIV testing among those consenting to the intervention was high, although linkage to care and ART initiation took longer than expected. Knowledge of HIV-positive status increased steeply after 1 y, almost attaining the first 90 target in women and approaching it in men. The second 90 target was more challenging, with approximately three-quarters of known HIV-positive individuals on ART by the end of the annual round. Achieving higher test uptake in men and more rapid linkage to care will be key objectives during the second annual round of the intervention.

Abstract  Full-text [free] access

Universal test, treat, and keep: improving ART retention is key in cost-effective HIV control in Uganda

McCreesh N, Andrianakis I, Nsubuga RN, Strong M, Vernon I, McKinley TJ, Oakley JE, Goldstein M, Hayes R, White RG. BMC Infect Dis. 2017 May 3;17(1):322. doi: 10.1186/s12879-017-2420-y.

Background: With ambitious new UNAIDS targets to end AIDS by 2030, and new WHO treatment guidelines, there is increased interest in the best way to scale-up ART coverage. We investigate the cost-effectiveness of various ART scale-up options in Uganda.

Methods: Individual-based HIV/ART model of Uganda, calibrated using history matching. 22 ART scale-up strategies were simulated from 2016 to 2030, comprising different combinations of six single interventions (1. increased HIV testing rates, 2. no CD4 threshold for ART initiation, 3. improved ART retention, 4. increased ART restart rates, 5. improved linkage to care, 6. improved pre-ART care). The incremental net monetary benefit (NMB) of each intervention was calculated, for a wide range of different willingness/ability to pay (WTP) per DALY averted (health-service perspective, 3% discount rate).

Results: For all WTP thresholds above $210, interventions including removing the CD4 threshold were likely to be most cost-effective. At a WTP of $715 (1 × per-capita-GDP) interventions to improve linkage to and retention/re-enrolment in HIV care were highly likely to be more cost-effective than interventions to increase rates of HIV testing. At higher WTP (> ~ $1690), the most cost-effective option was 'Universal Test, Treat, and Keep' (UTTK), which combines interventions 1-5 detailed above.

Conclusion: Our results support new WHO guidelines to remove the CD4 threshold for ART initiation in Uganda. With additional resources, this could be supplemented with interventions aimed at improving linkage to and/or retention in HIV care. To achieve the greatest reductions in HIV incidence, a UTTK policy should be implemented.

Abstract  Full-text [free] access

Predictors of loss to follow-up among patients on ART at a rural hospital in KwaZulu-Natal, South Africa.

Arnesen R, Moll AP, Shenoi SV. PLoS One. 2017 May 24;12(5):e0177168. doi: 10.1371/journal.pone.0177168. eCollection 2017

Introduction: Improved HIV outcomes as a result of expanded antiretroviral therapy (ART) access is threatened by increasing rates of loss to follow up (LTFU) among those on ART, largely reported in urban populations. Some reports suggest that LTFU rates are overestimated due to patient movement to other facilities and inadequate medical records.

Study Objective: To define the proportion disengaging from HIV care as well as the characteristics of those LTFU in order to design and implement appropriate interventions to increase retention.

Methods: We performed a retrospective review of patients who discontinued ART at a central hospital ART clinic in rural South Africa and compared with patients receiving care at the 15 primary health clinics (PHCs) to determine the true proportion of those who were LTFU. We also compared those who discontinued ART with those who did not at the central hospital ART clinic to determine predictors of loss to follow up.

Results: Among 3242 patients on ART, 820 were originally marked as LTFU. Among all patients, 272 (8.4%) were found at a clinic on treatment, 56 (1.7%) were found at a clinic from which they had since discontinued treatment, and 10 (0.3%) returned to care between June and July 2016, leaving 475 (14.7%) unaccounted for and thus categorized as 'true' LTFU. Factors found to be associated with discontinuation include being male, age 18-35, having a CD4 count under 200 cells/μL, and being on ART for under six months.

Conclusions: Young men with low CD4 counts early after ART initiation are at highest risk of ART disengagement in this rural South African HIV clinic. Novel interventions targeting this group are needed to improve retention in care.

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Ten-year trends in anti-retroviral therapy persistence among US Medicaid beneficiaries, 2001-2010

Youn B, Shireman TI, Lee Y, Galárraga O, Rana AI, Justice AC, Wilson IB. AIDS. 2017 May 16. doi: 10.1097/QAD.0000000000001541. [Epub ahead of print]

Objective: Whether the rate of HIV antiretroviral therapy (ART) persistence has improved over time in the U.S. is unknown. We examined ART persistence trends between 2001 and 2010, using non-HIV medications as a comparator.

Methods: We conducted a retrospective cohort study using Medicaid claims. We defined persistence as the duration of treatment from the first to the last fill date before a 90-day permissible gap, and used Kaplan-Meier curves and Cox proportional hazard models to assess crude and adjusted non-persistence. The secular trends of ART persistence in 43 598 HIV patients were compared with the secular trends of persistence with angiotensin-converting enzyme inhibitors (ACE) or angiotensin receptor blockers (ARB), statins, and metformin in (1) non-HIV-infected patients and (2) subgroups of HIV patients who started these control medications while using ART.

Results: Median time to ART non-persistence increased from 23.9 months in 2001-2003 to 35.4 months in 2004-2006, and was not reached for those starting ART in 2007-2010. In adjusted models, ART initiators in 2007-2010 had 11% decreased hazards of non-persistence compared with those who initiated in 2001-2003 (p < 0.001). For non-HIV patients initiating ACE/ARB, statins, and metformin, the hazard ratios (HR) for non-persistence comparing 2007-2010 to 2001-2003 were 1.07, 0.94, and 1.02, respectively (all p < 0.001). For HIV patients initiating the three control medications, the HRs of non-persistence comparing 2007-2010 to 2001-2003 were 0.71, 0.65, and 0.63, respectively (all p < 0.001).

Conclusions: Persistence with ART improved between 2001 and 2010. Persistence with control medications improved at a higher rate among HIV patients using ART than HIV-negative controls.

Abstract

Time from HIV diagnosis to commencement of antiretroviral therapy as an indicator to supplement the HIV cascade: Dramatic fall from 2011 to 2015

Medland NA, Chow EP, McMahon JH, Elliott JH, Hoy JF, Fairley CK. PLoS One. 2017 May 16;12(5):e0177634. doi: 10.1371/journal.pone.0177634. eCollection 2017.

Introduction:  The HIV care cascade is increasingly used to evaluate HIV treatment programs at the population level. However, the cascade indicators lack the ability to show changes over time, which reduces their utility to guide health policy. Alternatives have been proposed but are complex or result in a delay in results. We propose a new indicator of ART uptake, the time from HIV diagnosis to commencement of ART, and compare it to the existing cascade indicator of proportion of patients on treatment and the WHO proposed cohort cascade indicator of proportion of patients on treatment within one year of diagnosis.

Methods and Materials: Records from patients from the two largest HIV treatment centres in the state of Victoria, Australia (Melbourne Sexual Health Centre and The Alfred Hospital Department of Infectious Diseases) from 2011 to 2015 were extracted. The intervals between date of diagnosis, entry into care and initiation of ART were compared.

Results and Discussion: From 2011 to 2015 the proportion of in-care patients who were on ART rose from 87% to 93% (p<0.0001). From 2011 to 2014, the proportion of patients in care and on ART within one year of diagnosis increased from 43.4% to 78.9% (p = 0.001). The median time from diagnosis to ART fell from 418 days (IQR: 91-1176) to 77 days (IQR: 39-290)(p<0.001) by calendar year in which ART was commenced.

Conclusions: From 2011 to 2015 there were substantial and clinically important falls in the median time from diagnosis to commencing ART in those that commenced ART. The size of this dramatic change was not apparent when only reporting the proportion of patients on ART. Time to ART is a useful indicator and can be used to supplement existing cascade indicators in measuring progress toward universal ART coverage.

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Trends in prevalence of advanced HIV disease at antiretroviral therapy enrollment — 10 countries, 2004–2015

Auld AF, Shiraishi RW, Oboho I, Ross C, Bateganya M, Pelletier V, Dee J, Francois K, Duval N, Antoine M, Delcher C, Desforges G, Griswold M, Domercant JW, Joseph N, Deyde V, Desir Y, Van Onacker JD, Robin E, Chun H, Zulu I, Pathmanathan I, Dokubo EK, Lloyd S, Pati R, Kaplan J, Raizes E, Spira T, Mitruka K, Couto A, Gudo ES, Mbofana F, Briggs M, Alfredo C, Xavier C, Vergara A, Hamunime N, Agolory S, Mutandi G, Shoopala NN, Sawadogo S, Baughman AL, Bashorun A, Dalhatu I, Swaminathan M, Onotu D, Odafe S, Abiri OO, Debem HH, Tomlinson H, Okello V, Preko P, Ao T, Ryan C, Bicego G, Ehrenkranz P, Kamiru H, Nuwagaba-Biribonwoha H, Kwesigabo G, Ramadhani AA, Ng'wangu K, Swai P, Mfaume M, Gongo R, Carpenter D, Mastro TD, Hamilton C, Denison J, Wabwire-Mangen F, Koole O, Torpey K, Williams SG, Colebunders R, Kalamya JN, Namale A, Adler MR, Mugisa B, Gupta S, Tsui S, van Praag E, Nguyen DB, Lyss S, Le Y, Abdul-Quader AS, Do NT, Mulenga M, Hachizovu S, Mugurungi O, Barr BAT, Gonese E, Mutasa-Apollo T, Balachandra S, Behel S, Bingham T, Mackellar D, Lowrance D, Ellerbrock TV.MMWR Morb Mortal Wkly Rep. 2017 Jun 2;66(21):558-563. doi: 10.15585/mmwr.mm6621a3.

Monitoring prevalence of advanced human immunodeficiency virus (HIV) disease (i.e., CD4+ T-cell count <200 cells/μL) among persons starting antiretroviral therapy (ART) is important to understand ART program outcomes, inform HIV prevention strategy, and forecast need for adjunctive therapies. To assess trends in prevalence of advanced disease at ART initiation in 10 high-burden countries during 2004-2015, records of 694 138 ART enrollees aged ≥15 years from 797 ART facilities were analyzed. Availability of national electronic medical record systems allowed up-to-date evaluation of trends in Haiti (2004-2015), Mozambique (2004-2014), and Namibia (2004-2012), where prevalence of advanced disease at ART initiation declined from 75% to 34% (p<0.001), 73% to 37% (p<0.001), and 80% to 41% (p<0.001), respectively. Significant declines in prevalence of advanced disease during 2004-2011 were observed in Nigeria, Swaziland, Uganda, Vietnam, and Zimbabwe. The encouraging declines in prevalence of advanced disease at ART enrollment are likely due to scale-up of testing and treatment services and ART-eligibility guidelines encouraging earlier ART initiation. However, in 2015, approximately a third of new ART patients still initiated ART with advanced HIV disease. To reduce prevalence of advanced disease at ART initiation, adoption of World Health Organization (WHO)-recommended "treat-all" guidelines and strategies to facilitate earlier HIV testing and treatment are needed to reduce HIV-related mortality and HIV incidence.

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Advanced HIV disease in Botswana following successful antiretroviral therapy rollout: Incidence of and temporal trends in cryptococcal meningitis

Tenforde MW, Mokomane M, Leeme T, Patel RK, Lekwape N, Ramodimoosi C, Dube B, Williams EA, Mokobela KO, Tawanana E, Pilatwe T, Hurt WJ, Mitchell H, Banda DL, Stone H, Molefi M, Mokgacha K, Phillips H, Mullan PC, Steenhoff AP, Mashalla Y, Mine M, Jarvis JN. Clin Infect Dis. 2017 May 13. doi: 10.1093/cid/cix430. [Epub ahead of print].

Background: Botswana has a well-developed antiretroviral therapy (ART) program which serves as a regional model. With wide ART availability, the burden of advanced HIV and associated opportunistic infections would be expected to decline. We performed a nationwide surveillance study to determine the national incidence of cryptococcal meningitis, and describe characteristics of cases 2000-2014 and temporal trends at two national referral hospitals.

Methods: Cerebrospinal fluid data from all 37 laboratories performing meningitis diagnostics in Botswana were collected 2000-2014 to identify cases of cryptococcal meningitis. Basic demographic and laboratory data were recorded. Complete national data from 2013-2014 were used to calculate national incidence using UNAIDS population estimates. Temporal trends in cases were derived from national referral centers 2004-2014.

Results: 5296 episodes of cryptococcal meningitis were observed in 4702 individuals; 60.6% were male, and median age was 36 years. Overall 2013-2014 incidence was 17.8 cases/100 000 person-years (95%CI 16.6 - 19.2). In the HIV-infected population, incidence was 96.8 cases/100 000 person-years (95%CI 90.0 - 104.0); male predominance was seen across CD4 strata. At national referral hospitals, cases decreased 2007-2009 but stabilized 2010-2014.

Conclusions: Despite excellent ART coverage in Botswana, there is still a substantial burden of advanced HIV, with 2013-2014 incidence of cryptococcal meningitis comparable to pre-ART era rates in South Africa. Our findings suggest a key population of individuals, often men, are developing advanced disease and associated opportunistic infections due to a failure to effectively engage in care, highlighting the need for differentiated care models.

Abstract

Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies

Trickey A, May MT, Vehreschild JJ, Obel N, Gill MJ, Crane HM, Boesecke C, Patterson S, Grabar S, Cazanave C, Cavassini M, Shepherd L, Monforte AD, van Sighem A, Saag M, Lampe F, Hernando V, Montero M, Zangerle R, Justice AC, Sterling T, Ingle SM, Sterne JAC (Antiretroviral Therapy Cohort Collaboration). Lancet HIV. 2017 May 10. pii: S2352-3018(17)30066-8. doi: 10.1016/S2352-3018(17)30066-8. [Epub ahead of print]

Background: Health care for people living with HIV has improved substantially in the past two decades. Robust estimates of how these improvements have affected prognosis and life expectancy are of utmost importance to patients, clinicians, and health-care planners. We examined changes in 3 year survival and life expectancy of patients starting combination antiretroviral therapy (ART) between 1996 and 2013.

Methods: We analysed data from 18 European and North American HIV-1 cohorts. Patients (aged ≥16 years) were eligible for this analysis if they had started ART with three or more drugs between 1996 and 2010 and had at least 3 years of potential follow-up. We estimated adjusted (for age, sex, AIDS, risk group, CD4 cell count, and HIV-1 RNA at start of ART) all-cause and cause-specific mortality hazard ratios (HRs) for the first year after ART initiation and the second and third years after ART initiation in four calendar periods (1996-99, 2000-03 [comparator], 2004-07, 2008-10). We estimated life expectancy by calendar period of initiation of ART.

Findings: 88 504 patients were included in our analyses, of whom 2106 died during the first year of ART and 2302 died during the second or third year of ART. Patients starting ART in 2008-10 had lower all-cause mortality in the first year after ART initiation than did patients starting ART in 2000-03 (adjusted HR 0·71, 95% CI 0·61-0·83). All-cause mortality in the second and third years after initiation of ART was also lower in patients who started ART in 2008-10 than in those who started in 2000-03 (0·57, 0·49-0·67); this decrease was not fully explained by viral load and CD4 cell count at 1 year. Rates of non-AIDS deaths were lower in patients who started ART in 2008-10 (vs 2000-03) in the first year (0·48, 0·34-0·67) and second and third years (0·29, 0·21-0·40) after initiation of ART. Between 1996 and 2010, life expectancy in 20-year-old patients starting ART increased by about 9 years in women and 10 years in men.

Interpretation: Even in the late ART era, survival during the first 3 years of ART continues to improve, which probably reflects transition to less toxic antiretroviral drugs, improved adherence, prophylactic measures, and management of comorbidity. Prognostic models and life expectancy estimates should be updated to account for these improvements.

Abstract  Full-text [free] access

 

Africa, Asia, Europe, Northern America, Oceania
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H*V – can we do better for HIV, HBV and HCV if we all work together?

Editor’s notes: The Sustainable Development Goals (SDGs) signal a major shift in the way that the United Nations and her development partners aim to shape the next decades.  Whereas the Millennium Development Goals reinforced specific programmes for HIV, tuberculosis and malaria, the SDGs call for a more integrated approach to health and well-being and encourage integration and synergy wherever it makes sense.  Hepatitis is one obvious area in which better collaboration and coordination could yield benefits.  Hepatitis B (HBV) and C (HCV) viruses are both more common in some of the populations most affected by HIV.  HCV can now be cured with drugs that derive directly from the HIV portfolio, while some ARVs have a direct effect on HBV.

Rwanda is one of the first countries in sub-Saharan Africa to set up a control programme for viral hepatitis, building on the infrastructure established for HIV. Umutesi and colleagues report on results of screening almost 120 000 people living with HIV who entered care for markers of HBV and HCV.  Around 5000 people (4.3%) were identified with a positive Hepatitis B surface antigen and a similar number (4.6%) were found to have antibodies against HCV.  There was marked variation geographically with a range by district from 2%-11% for HBV, higher in more urban areas and in men.  For HCV the range was from 3%-8% and was higher in more rural areas, and also in men.  This study provides a good platform to estimate numbers of people who might need treatment and to plan the next steps in an integrated programme.

People who inject drugs are particularly severely affected by HCV, and so co-infection with both HIV and HCV is common in areas where both viruses circulate.  Some estimates from Ho Chi Minh City in Viet Nam suggest that more than 40% of people who inject drugs are living with HIV and that essentially all of these people are also co-infected with HCV.  Birger R and colleagues developed a mathematical model to explore the likely impact of interventions aimed at HIV, HCV or broad harm reduction [with methadone maintenance treatment (MMT)] on future mortality and incidence of both infections.  While ART scale up reduces HIV incidence and mortality, it has no effect on HCV.  MMT is effective at reducing incidence of both HIV and HCV (and has morbidity and mortality benefits beyond these viruses).  However, MMT does not help the many people already living with HCV and so has little effect on HCV related mortality. So the model is clear that treatment for HCV needs to be an important part of a combined programme and that we urgently need to find ways to reduce the price of directly acting antivirals if we are to save more Vietnamese lives.

Haldane and colleagues have also focused on this intersection between HIV and substance use services.  They carried out a systematic review to understand the models and implications of integration of service delivery.  The authors expand their typology of integration models considering the point of entry of the client, and the degree to which services are co-located and delivered.  Integration can be considered as “clinical”, “service” or “systems”.  The first two can operate at the micro or meso level meaning that individual staff can deal with both situations, or that staff are trained to provide appropriate referrals.  Systems level integration operates at a macro level and implies that programmes for each service make collaborations and coordinate in ways that may affect staffing, funding and fragmentation of services. Although there are theoretical advantages to coordination and integration (as shown by the mathematical model above), there are few good empirical studies of integrated service delivery reported outside the USA.  The authors considered that most of the intervention studies had a risk of bias in the interpretation of their impact, although all demonstrated positive changes in outcomes.  Furthermore, almost all the studies focussed on integration at the clinic or individual provider level (meso or micro) rather than addressing the larger systemic challenges that we need to consider.  If we are to achieve the ideals laid out in the Sustainable Development Goals, we will need to overcome some of these systemic challenges, particularly for populations that are criminalized and marginalized by many of the public services.

Prevalence of hepatitis B and C infection in persons living with HIV enrolled in care in Rwanda.

Umutesi J, Simmons B, Makuza JD, Dushimiyimana D, Mbituyumuremyi A, Uwimana JM, Ford N, Mills EJ, Nsanzimana S. BMC Infect Dis. 2017 May 2;17(1):315. doi: 10.1186/s12879-017-2422-9.

Background: Hepatitis B (HBV) and C (HCV) are important causes of morbidity and mortality in people living with human immunodeficiency virus (HIV). The burden of these co-infections in sub-Saharan Africa is still unclear. We estimated the prevalence of the hepatitis B surface antigen (HBsAg) and hepatitis C antibody (HCVAb) among HIV-infected individuals in Rwanda and identified factors associated with infection.

Methods: Between January 2016 and June 2016, we performed systematic screening for HBsAg and HCVAb among HIV-positive individuals enrolled at public and private HIV facilities across Rwanda. Results were analyzed to determine marker prevalence and variability by demographic factors.

Results: Overall, among 117 258 individuals tested, the prevalence of HBsAg and HCVAb was 4.3% (95% confidence interval [CI] (4.2-4.4) and 4.6% (95% CI 4.5-4.7) respectively; 182 (0.2%) HIV+ individuals were co-infected with HBsAg and HCVAb. Prevalence was higher in males (HBsAg, 5.4% [5.1-5.6] vs. 3.7% [3.5-3.8]; HCVAb, 5.0% [4.8-5.2] vs. 4.4% [4.3-4.6]) and increased with age; HCVAb prevalence was significantly higher in people aged ≥65 years (17.8% [16.4-19.2]). Prevalence varied geographically.

Conclusion: HBV and HCV co-infections are common among HIV-infected individuals in Rwanda. It is important that viral hepatitis prevention and treatment activities are scaled-up to control further transmission and reduce the burden in this population. Particular efforts should be made to conduct targeted screening of males and the older population. Further assessment is required to determine rates of HBV and HCV chronicity among HIV-infected individuals and identify effective strategies to link individuals to care and treatment.

Abstract  Full-text [free] access

The impact of HCV therapy in a high HIV-HCV prevalence population: A modeling study on people who inject drugs in Ho Chi Minh City, Vietnam.

Birger RB, Le T, Kouyos RD, Grenfell BT, Hallett TB. PLoS One. 2017 May 11;12(5):e0177195. doi: 10.1371/journal.pone.0177195. eCollection 2017.

Background: Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) coinfection is a major global health problem especially among people who inject drugs (PWID), with significant clinical implications. Mathematical models have been used to great effect to shape HIV care, but few have been proposed for HIV/HCV.

Methods: We constructed a deterministic compartmental ODE model that incorporated layers for HIV disease progression, HCV disease progression and PWID demography. Antiretroviral therapy (ART) and Methadone Maintenance Therapy (MMT) scale-ups were modeled as from 2016 and projected forward 10 years. HCV treatment roll-out was modeled beginning in 2026, after a variety of MMT scale-up scenarios, and projected forward 10 years.

Results: Our results indicate that scale-up of ART has a major impact on HIV though not on HCV burden. MMT scale-up has an impact on incidence of both infections. HCV treatment roll-out has a measurable impact on reductions of deaths, increasing multifold the mortality reductions afforded by just ART/MMT scale-ups.

Conclusion: HCV treatment roll-out can have major and long-lasting effects on averting PWID deaths on top of those averted by ART/MMT scale-up. Efficient intervention scale-up of HCV alongside HIV interventions is critical in Vietnam.

Abstract  Full-text [free] access 

Integrating HIV and substance use services: a systematic review

Haldane V, Cervero-Liceras F, Chuah FL, Ong SE, Murphy G, Sigfrid L, Watt N, Balabanova D, Hogarth S, Maimaris W, Buse K, Piot P, McKee M, Perel P, Legido-Quigley H. Journal of the International AIDS Society. 2017 May 30;20(1).http://dx.doi.org/10.7448/IAS.20.1.21585.

Introduction: Substance use is an important risk factor for HIV, with both concentrated in certain vulnerable and marginalized populations. Although their management differs, there may be opportunities to integrate services for substance use and HIV. In this paper we systematically review evidence from studies that sought to integrate care for people living with HIV and substance use problems.

Methods: Studies were included if they evaluated service integration for substance use and HIV. We searched multiple databases from inception until October 2015. Articles were screened independently by two reviewers and assessed for risk of bias.

Results and discussion: 11 057 records were identified, with 7616 after removal of duplicates. After screening titles and abstracts, 51 met the inclusion criteria. Integration models were categorized by location (HIV, substance use and other facilities), level of integration from micro (integrated care delivered to individuals) to macro (system level integrations) and degree of integration from least (screening and counselling only) to most (care for HIV, substance use and/or other illnesses at the same facility). Most reported descriptive or cohort studies; in four randomized control trials integrated activities improved patient outcomes. There is potential for integrating services at all facility types, including mobile health services. While services offering screening only can achieve synergies, there are benefits from delivering integrated treatment for HIV and substance use, including ease of referral to other mental health and social services.

Conclusions: Our review used a wide range of databases and conference archives to increase representation of papers from low- and middle-income countries. Limitations include the overrepresentation of studies from the United States, and the descriptive nature of the majority of papers. The evidence reviewed shows that greater integration offers important benefits in both patient and service outcomes but further research and outcome reporting is needed to better understand innovative and holistic care models at the complex intersection of substance use and HIV services.

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Africa, Asia, Europe, Northern America
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How do we know which activities make a difference to HIV prevention?

Editor’s notes: In order to be fairly certain that an intervention is responsible for changes in HIV or HIV-related behaviours, the gold standard is randomization. This allows for fair comparisons between groups, since factors that might alter the outcomes will be more or less equally balanced between the study groups.  This is true whether such confounding factors are expected, but also importantly, even those factors that are unknown, unexpected and unmeasured will also be balanced between the arms. 

A second key determinant of high quality research is to use an approach that maximizes full engagement and follow-up of participants in the study.  One such approach that is widely recognized is to use Good Participatory Practice.  

Rhodes and colleagues study condom promotion and HIV testing among the Hispanic/Latino community of gay men and other men who have sex with men in North Carolina, USA.  Although gay men and other men who have sex with men represent approximately 4% of the adult male population in the United States of America, they account for more than 80% of new HIV infections among men.  Around one quarter of gay men and other men who have sex with men are Hispanic or Latino.  The authors therefore wanted to use research to make a difference to the HIV burden of the Hispanic/Latino gay men and other men who have sex with men community in North Carolina, USA.  They found that despite the impact of HIV on Hispanic/ Latino gay men and other men who have sex with men, they were only able to identify one evidence-based behavioural HIV prevention programme focussed on this population.

The authors used an extensive community based participatory research partnership, whose members represented the Hispanic/ Latino gay men and other men who have sex with men community, AIDS service organizations, Hispanic/Latino-serving community organizations, and universities to develop, implement, and evaluate a Spanish-language, small group intervention designed to increase condom use and HIV testing among Hispanic/Latino gay men and other men who have sex with men (HOLA en Grupos).

304 participants were randomly allocated to the HOLA en Grupos intervention, or to a general health education comparison intervention having the same number of sessions (4) and duration (16 hours in total) that focussed on prostate, lung, and colorectal cancers; diabetes; high cholesterol; cardiovascular disease; and alcohol misuse. These topics for the control group were identified on the basis of identified needs and priorities of Hispanic/Latino gay men and other men who have sex with men.

HOLA en Grupos is grounded on social cognitive theory, empowerment education, and traditional Hispanic/Latino cultural values and includes four interactive modules of four hours each delivered in groups.  Participants in both intervention and control arms received reimbursement for their time, certificates of completion and meals and a celebration at the completion of the course.  In other words this was an intensive intervention that might be hard to replicate in most settings, but it follows very high standards both for developing and conducting the research and also for determining the impact of the intervention.

The intervention was associated with a large effect on both condom usage (four-fold higher in the intervention arm than the control) and HIV test uptake (an astonishing 14-fold higher, reflecting the relatively low testing rate in the control group).

A major limitation in many HIV prevention studies, including this one, is that the outcome is based on reported behaviour.  The challenge is that the real outcome of interest, which is new HIV infections, is relatively rare in almost all communities so that studies have to be huge and expensive, and the large majority of participants in both intervention and control arms do not in fact acquire HIV.  This is in contrast to most studies of treatment, where there are clearly defined biological, standardized measures which many or all participants are likely to reach.  Nonetheless, there are many examples of studies that find changes in reported behaviour that are not associated with biological markers of such change (such as incidence of HIV or other sexually transmitted infections, or pregnancy). 

There are also many observational or ecological studies that report changes in new HIV infections but that cannot truly say why the number of infections fell and whether the interventions used in the study were responsible for the changes.  For example Nwokolo and colleagues report in a short research letter on the dramatic decline in new HIV diagnoses in the large London clinic where they work.  New infections in that clinic, and in fact in other large clinics in London, have dropped by a remarkable 40% from 2015 to 2016, as originally reported in the popular science press before any scientific publication or presentation. The authors of the research letter are suitably cautious about how to account for the impressive decline.  Various systems have been improved over the past few years in this clinic to make it easier to have an HIV test and start treatment immediately.  However, most of the clinic team (and many other commentators) assume that it is also due to the rapid rise in the use of PrEP.  Although it is still not available through the UK National Health Service, the clinic has been at the forefront of encouraging gay men and other men who have sex with men who might benefit from PrEP to purchase it from on-line pharmacies.  The clinic then provides the appropriate monitoring and follow up to ensure that their clients get the best possible PrEP service given the current constraints.  Whatever the cause, we should be celebrating the rapid fall in new HIV infections across London, which is home to a substantial proportion of the new HIV infections in the UK.

The challenges of demonstrating evidence of effectiveness for HIV prevention is also felt among black women in the USA.  Although they have the highest burden of HIV among women in the USA, the incidence rates are such that a traditional randomized trial design would need to be huge, and consequently hugely expensive.  Adimora and colleagues consider whether an alternative trial design might be to use data from high HIV incidence settings and then to develop proxies of protection, such as the concentration of a PrEP medicine to infer whether black women are protected.  An alternative that has been proposed for men who have sex with men would be to look for other markers of high risk, such as sexually transmitted infections, reported partners, age, and substance use and estimate the likely risk of HIV acquisition in the absence of PrEP from these parameters.  Then the observed incidence could be compared to this modelled counterfactual, much as was done in the open label extension of the Partners PrEP study in Kenyan and Ugandan sero-different couples.  However, translating risk factors for infection across populations, and even continents when there is such heterogeneity in risk of infection is not at all straightforward.  So there is still plenty to think about and no clear answers yet!

A useful addition to the tool box for designing studies and assessing the effectiveness of interventions, would be better tools for measuring recent infection.  There are several assays all with differing characteristics but increasingly these differences and how they interact with different clades of HIV are becoming clear.  Key determinants for each assay are the mean duration of recent infection (MDRI) estimate (which does seem to vary by clade) and the false recency rate (FRR) which needs to be less than 2% to be considered useful.  Hargrove and colleagues used three different assays to test samples from 101 women who seroconverted during the ZVITAMBO trial.  The MDRI measured using standard cut-off points, were considerably shorter than those published for the general population.  The authors point out that changes in antibody properties among women who have recently given birth or other unspecified physiological states, mean that incidence assays may give different results from those published and expected.  Yet more caution when comparing incidence estimates between studies.  As an endpoint in a comparison between two groups in the same population, the assays are still attractive. Although, given typical MDRIs of around six to nine months, these assays will still need to be embedded in very large samples to give reliable estimates of incidence and statistically significant differences between groups.

This month saw the production of a useful supplement on many aspects of how data from different sources, including incidence assays are used to inform the sophisticated models on which so much HIV planning, programming and financing is based.  An example is Mahiane and colleagues’ paper on the development of a new tool to fit existing programme data into the spectrum suite of models in order to estimate incidence.

Finally in this section, for those who are keen on laboratory studies, Richardson-Harman and colleagues describe the current state of ex-vivo challenge models for assessing potential candidates as microbicides.  In these models, biopsies of rectal, cervical or vaginal tissue, taken during other procedures, or from volunteers, are kept alive in the laboratory.  The tissues can then be challenged with HIV in the presence or absence of potential microbicide products.  The current model works best for rectal tissues, in which infection occurs promptly and consistently, so that the effect of a microbicide can clearly be seen by a reduction in the production of HIV p24 antigen.  However, for cervical and vaginal tissues, the infection (in the absence of any microbicide) was less consistent, slower and lasted longer making it less easy to determine statistical differences between those tissues with microbicide and those without.  Further work of this sort may help to streamline the choice of microbicide or PrEP products that can most sensibly be taken out of the laboratory and into the (almost) real world of clinical trials.

Small-group randomized controlled trial to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men.

Rhodes SD, Alonzo J, Mann L, Song EY, Tanner AE, Arellano JE, Rodriguez-Celedon R, Garcia M, Freeman A, Reboussin BA, Painter TM. Am J Public Health. 2017 Jun;107(6):969-976. doi: 10.2105/AJPH.2017.303814. Epub 2017 Apr 20.

Objectives: To evaluate the HOLA en Grupos intervention, a Spanish-language small-group behavioral HIV prevention intervention designed to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men.

Methods: In 2012 to 2015, we recruited and randomized 304 Hispanic/Latino men who have sex with men, aged 18 to 55 years in North Carolina, to the 4-session HOLA en Grupos intervention or an attention-equivalent general health education comparison intervention. Participants completed structured assessments at baseline and 6-month follow-up. Follow-up retention was 100%.

Results: At follow-up, relative to comparison participants, HOLA en Grupos participants reported increased consistent condom use during the past 3 months (adjusted odds ratio [AOR] = 4.1; 95% confidence interval [CI] = 2.2, 7.9; P < .001) and HIV testing during the past 6 months (AOR = 13.8; 95% CI = 7.6, 25.3; P < .001). HOLA en Grupos participants also reported increased knowledge of HIV (P < .001) and sexually transmitted infections (P < .001); condom use skills (P < .001), self-efficacy (P < .001), expectancies (P < .001), and intentions (P < .001); sexual communication skills (P < .01); and decreased fatalism (P < .001).

Conclusions: The HOLA en Grupos intervention is efficacious for reducing HIV risk behaviors among Hispanic/Latino men who have sex with men.

Abstract access 

Not just PrEP: other reasons for London's HIV decline.

Nwokolo N, Whitlock G, McOwan A. Lancet HIV. 2017 Apr;4(4):e153. doi: 10.1016/S2352-3018(17)30044-9.

The reduction in HIV diagnoses in London in 2016 is attributed to pre-exposure prophylaxis (PrEP). We believe that the causes of the 42% decline seen at our clinic are likely to be multifactorial. 56 Dean Street diagnoses one in four of London's HIV cases, 50% of whom have incident infection (ie, within 4 months of infection). Because of this, and following the results of the START study, we actively recommend treatment at, or close to, diagnosis, reducing the risk of transmission in people who would otherwise be highly infectious.

Abstract access 

US black women and HIV prevention: time for new approaches to clinical trials.

Adimora AA, Cole SR, Eron JJ Clin Infect Dis. 2017 Apr 5. doi: 10.1093/cid/cix313. [Epub ahead of print]. 

Black women bear the highest burden of HIV infection among US women. Tenofovir/ emtricitabine HIV prevention trials among women in Africa have yielded varying results. Ideally, a randomized controlled trial (RCT) among US women would provide data for guidelines for US women's HIV pre-exposure prophylaxis use. However, even among US black women at high risk for HIV infection, sample size requirements for an RCT with HIV incidence as its outcome are prohibitively high. We propose to circumvent this large sample size requirement by evaluating relationships between HIV incidence and drug concentrations measured among participants in traditional phase 3 trials in high incidence settings - and then applying these observations to drug concentrations measured among at risk individuals in lower incidence settings, such as US black women. This strategy could strengthen the evidence base to enable black women to fully benefit from prevention research advances and decrease racial disparities in HIV rates.

Abstract access 

Heightened HIV antibody responses in postpartum women as exemplified by recent infection assays: implications for incidence estimates.

Hargrove JW, van Schalkwyk C, Humphrey JH, Mutasa K, Ntozini R, Owen SM, Masciotra S, Parekh BS, Duong YT, Dobbs T, Kilmarx PH, Gonese E. AIDS Res Hum Retroviruses. 2017 May 24. doi: 10.1089/AID.2016.0319. [Epub ahead of print].

Laboratory assays that identify recent HIV infections are important for assessing impacts of interventions aimed at reducing HIV incidence. Kinetics of HIV humoral responses can vary with inherent assay properties, and between HIV subtypes, populations, and physiological states. They are important in determining mean duration of recent infection (MDRI) for antibody-based assays for detecting recent HIV infections. We determined MDRIs for multi-subtype peptide representing subtypes B, E and D (BED)-capture enzyme immunoassay, limiting antigen (LAg), and Bio-Rad Avidity Incidence (BRAI) assays for 101 seroconverting postpartum women, recruited in Harare from 1997 to 2000 during the Zimbabwe Vitamin A for Mothers and Babies trial, comparing them against published MDRIs estimated from seroconverting cases in the general population. We also compared MDRIs for women who seroconverted either during the first 9 months, or at later stages, postpartum. At cutoffs (C) of 0.8 for BED, 1.5 for LAg, and 40% for BRAI, estimated MDRIs for postpartum mothers were 192, 104, and 144 days, 33%, 32%, and 52% lower than published estimates of 287, 152 and 298 days, respectively, for clade C samples from general populations. Point estimates of MDRI values were 7%-19% shorter for women who seroconverted in the first 9 months postpartum than for those seroconverting later. MDRI values for three HIV incidence biomarkers are longer in the general population than among postpartum women, particularly those who recently gave birth, consistent with heightened immunological activation soon after birth. Our results provide a caution that MDRI may vary significantly between subjects in different physiological states.

Abstract access 

Improvements in Spectrum's fit to program data tool.

Mahiane SG, Marsh K, Grantham K, Crichlow S, Caceres K, Stover J.  AIDS. 2017 Apr;31 Suppl 1:S23-S30. doi: 10.1097/QAD.0000000000001359.

Objective: The Joint United Nations Program on HIV/AIDS-supported Spectrum software package (Glastonbury, Connecticut, USA) is used by most countries worldwide to monitor the HIV epidemic. In Spectrum, HIV incidence trends among adults (aged 15-49 years) are derived by either fitting to seroprevalence surveillance and survey data or generating curves consistent with program and vital registration data, such as historical trends in the number of newly diagnosed infections or people living with HIV and AIDS related deaths. This article describes development and application of the fit to program data (FPD) tool in Joint United Nations Program on HIV/AIDS' 2016 estimates round.

Methods: In the FPD tool, HIV incidence trends are described as a simple or double logistic function. Function parameters are estimated from historical program data on newly reported HIV cases, people living with HIV or AIDS-related deaths. Inputs can be adjusted for proportions undiagnosed or misclassified deaths. Maximum likelihood estimation or minimum chi-squared distance methods are used to identify the best fitting curve. Asymptotic properties of the estimators from these fits are used to estimate uncertainty.

Results: The FPD tool was used to fit incidence for 62 countries in 2016. Maximum likelihood and minimum chi-squared distance methods gave similar results. A double logistic curve adequately described observed trends in all but four countries where a simple logistic curve performed better.

Conclusion: Robust HIV-related program and vital registration data are routinely available in many middle-income and high-income countries, whereas HIV seroprevalence surveillance and survey data may be scarce. In these countries, the FPD tool offers a simpler, improved approach to estimating HIV incidence trends.

Abstract access 

Analytical advances in the ex vivo challenge efficacy assay.

Richardson-Harman N, Parody R, Anton P, McGowan I, Doncel G, Thurman AR, Herrera C, Kordy K, Fox J, Tanner K, Swartz G, Dezzutti CS. AIDS Res Hum Retroviruses. 2017 Apr;33(4):395-403. doi: 10.1089/AID.2016.0073. Epub 2016 Dec 16.

The ex vivo challenge assay is being increasingly used as an efficacy endpoint during early human clinical trials of HIV prevention treatments. There is no standard methodology for the ex vivo challenge assay, although the use of different data collection methods and analytical parameters may impact results and reduce the comparability of findings between trials. In this analysis, we describe the impact of data imputation methods, kit type, testing schedule and tissue type on variability, statistical power, and ex vivo HIV growth kinetics. Data were p24 antigen (pg/ml) measurements collected from clinical trials of candidate microbicides where rectal (n = 502), cervical (n = 88), and vaginal (n = 110) tissues were challenged with HIV-1BaL ex vivo. Imputation of missing data using a nonlinear mixed effect model was found to provide an improved fit compared to imputation using half the limit of detection. The rectal virus growth period was found to be earlier and of a relatively shorter duration than the growth period for cervical and vaginal tissue types. On average, only four rectal tissue challenge assays in each treatment and control group would be needed to find a one log difference in p24 to be significant (alpha = 0.05), but a larger sample size was predicted to be needed for either cervical (n = 21) or vaginal (n = 10) tissue comparisons. Overall, the results indicated that improvements could be made in the design and analysis of the ex vivo challenge assay to provide a more standardized and powerful assay to compare efficacy of microbicide products.

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Non-communicable diseases and co-morbidities – the flip side of successful ART programmes?

Editor’s notes: As the population of people living with HIV grows older and lives longer, the importance of non-communicable diseases is increasing.  Several studies this month explored various aspects of this intersection.

An encouraging study from Spain by Sorigué M et al., analysed the outcomes of patients with advanced stage Hodgkin’s lymphoma, a relatively common cancer both among people living with HIV and the HIV-negative population. The authors showed that, in the era of combined antiretroviral therapy, the complete response rate and ten year survival were not significantly different among people living with HIV (89% and 73%) and HIV negative people (91% and 68%).

Another broadly encouraging study from Ireland by Tinago W et al., followed up 384 people (176 living with HIV) to determine changes over three years in their bone mineral density (BMD).  BMD was somewhat lower in the people living with HIV, despite the group being younger on average.  As expected, BMD gradually fell with increasing age but the rate of bone loss was no different between people living with HIV and HIV negative people.  88% of the people living with HIV were on ART at the start of the study period.  Not having started ART among people living with HIV was associated with lower BMD and people who had started more recently showed the largest declines in BMD.  This suggests (as has previously been shown in cohorts of people living with HIV) that after an initial loss in BMD, the rate of loss stabilizes and is similar to HIV-negative people.  Interestingly, the authors did not show that overall exposure to tenofovir disproxil fumarate (TDF) was particularly associated with greater BMD loss over the course of follow up, despite several previous randomized trials confirming that TDF does cause BMD loss when it is started.

While on the subject of TDF, this month saw two important regulatory trials of tenofovir alafenamide (TAF), sponsored by the manufacturers Gilead Sciences.  630 people living with HIV on treatment with rilpivirine, emtricitabine and TDF whose viral load was supressed, were randomly allocated to remain on the same regimen or to swap the TDF for TAF.  TAF is a pro-drug, that reduces the plasma concentrations of tenofovir and is therefore expected to reduce the renal and bone toxicities associated with TDF while still delivering active drug to the cells where it is needed.  One year later, viral suppression was very similar in the two groups (94%).  There was also no significant difference seen in the side effects over this one year period, with no serious adverse events and 6% vs. 12% having some side effects in the TAF and TDF arms respectively [Orkin C and colleagues].

A related study by DeJesus E et al. with the same design was conducted among people taking efavirenz, emtricitabine and tenofovir, one of the most common first line regimens throughout the world. In this trial the efavirenz was switched to rilpivirine and the TDF to TAF.  875 people living with HIV whose viral load was supressed were randomized and after one year viral suppression was very similar in the two groups (90-92%).  There was also no significant difference seen in the side effects over this one year period, with no serious adverse events and 13% vs. 10% having some side effects in the rilpivirine -TAF and efavirenz-TDF arms respectively.

Returning to co-morbidities and non-communicable diseases, a study by Rodríguez-Arbolí E and colleagues in rural Tanzania has shown that 11.6% of people living with HIV who had not yet started ART had raised blood pressure.  A further 9.6% develop raised blood pressure during follow up, an incidence of 12 per 100 person years. The risk factors for developing hypertension were those well recognized in HIV-negative populations (age, renal disease and being overweight) and not specifically related to HIV infection, ART or immunological status.  The authors recommend integration of non-communicable disease screening and management into HIV care clinics but a larger conclusion might be to improve management of hypertension more generally, as it affects both people living with HIV and people without.

In contrast, a study by Pollack TM et al. from Viet Nam shows that smoking tobacco is associated with a higher viral load among people living with HIV presenting for ART.  As would be expected, other predictors of more advanced HIV disease such as lower CD4 counts and lower BMI and prior TB were all associated with a higher viral load at presentation.  Male sex was also significantly associated with a higher viral load.  The authors point out various other studies from Cameroon and the US that have shown similar and related interactions between smoking tobacco, viral load at presentation or viral load suppression or rebound on ART treatment.  Other studies in the US have not found this association.  One of the challenges is to separate behavioural factors that might be confounders – perhaps people who smoke are more likely to present late.  In this study there was not a clear dose response.  People who smoked more than ten cigarettes per day were actually somewhat less likely in this sample to have a higher viral load than people who smoked 1-10 cigarettes per day, but the numbers were too small to make statistically significant claims.  The authors suggest that oxidative stress and induction of the cytochrome P450 (CYP) pathway could explain the mechanism of smoking-related increased VL among HIV positive individuals.  While the study cannot prove cause and effect, there are already many reasons to promote tobacco cessation among people living with HIV and this may be an additional one.

The D:A:D study is a major prospective cohort that follows more than 49 000 people living with HIV in Europe, Australia and the USA.  Among the cohort, more than 4000 have developed chronic renal impairment.  A study by Ryom L et al. this month examined whether there was improvement, stabilisation or progression of renal impairment in the 2006 individuals who had additional measurements 2-3 years after renal impairment was first noted and explored risk factors for each.  On the one hand, they show that some ARVs (notably TDF and ritonavir-boosted atazanovir) are associated with worse renal outcomes, but on the other hand, they demonstrate that after stopping these nephrotoxic medicines, the kidneys recover or at least do not deteriorate further.  Once again, traditional risk factors (older age, high blood pressure and diabetes) are also important risk factors for the kidneys of people living with HIV.  As the population of people living with HIV gets older and lives longer, HIV care and traditional non-communicable disease management must overlap and coordinate.

HIV-infection has no prognostic impact on advanced-stage Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine and dacarbazine.

Sorigué M, García O, Tapia G, Baptista MJ, Moreno M, Mate JL, Sancho JM, FeliuE, Ribera JM, Navarro JT. AIDS. 2017 Mar 29. doi: 10.1097/QAD.0000000000001487. [Epub ahead of print]

Objective: Classical Hodgkin lymphoma (cHL) is a non-AIDS-defining cancer with good response to chemotherapy in the combined antiretroviral therapy (cART) era. The aim of the study was to compare the characteristics, the response with treatment and survival of advanced-stage cHL treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) between cART-treated HIV-positive and HIV-negative patients.

Design and methods: We retrospectively analyzed advanced-stage cHL patients from a single institution, uniformly treated with ABVD. All HIV-positive patients received cART concomitantly with ABVD.

Results: A total of 69 patients were included in the study: 21 were HIV-positive and 48 were HIV-negative. HIV-positive patients had more aggressive features at cHL diagnosis, such as worse performance status, more frequent bone marrow involvement and mixed cellularity histologic subtype. There were no differences in complete response rate (89% in HIV-positive vs. 91% in HIV-negative), P = 1; disease-free survival 10-year disease-free survival 70% (41-99%) vs. 74% (57-91%), P = 0.907 and overall survival (OS) 10-year OS 73% (95% confidence interval52-94%) vs. 68% (51-85%), P = 0.904. On multivariate analysis, HIV infection did not correlate with worse OS.

Conclusion: Although HIV-positive patients with cHL had more aggressive baseline features in this series, there were no differences in response rate or survival between HIV-positive and HIV-negative patients.

Abstract access 

Predictors of longitudinal change in bone mineral density in a cohort of HIV-positive and negative patients.

Tinago W, Cotter AG, Sabin CA, Macken A, Kavanagh E, Brady JJ, McCarthy G,Compston J, Mallon PW; HIV UPBEAT Study Group.225. AIDS. 2017 Mar 13;31(5):643-652. doi: 10.1097/QAD.0000000000001372.

Objective: Although low bone mineral density (BMD) is prevalent in HIV, changes in BMD over time remain unclear. We aimed to compare rates of, and factors associated with, BMD change between HIV-positive and HIV-negative patients.

Methods: In a prospective, 3-year cohort, HIV-positive and HIV-negative patients provided annual demographic and clinical data, fasting bloods, and dual x-ray absorptiometry. Using longitudinal mixed models we compared and determined predictors of rate of change in BMD.

Results: Of 384 study participants (45.8% HIV positive), 120 contributed two and 264 contributed three BMD measurements. Those with HIV were younger [median interquartile range 39 (34-46) vs. 43 (35-50) years; P = 0.04], more often men (61 vs. 46%; P = 0.003), and less likely Caucasian (61 vs. 82%; P < 0.001).Although BMD was lower in those with HIV, BMD declined in both groups, with nonsignificant between-group difference in rate of BMD change over time. Within the HIV group, starting antiretroviral therapy (ART) within 3 months of enrolment was associated with greater BMD decline at all anatomical sites (all P < 0.001). Age more than 30 years, Caucasian ethnicity, and not being on ART during follow-up were associated with greater decline and higher parathyroid hormone associated with a smaller decline in BMD at the femoral neck. We found no association between BMD change and exposure to tenofovir disoproxil fumarate or protease inhibitors.

Conclusion: We observed no difference in rate of BMD decline regardless of HIV status and in HIV-positive patient, having started ART within the previous 3 months was the only factor associated with greater BMD decline at all three sites.

Abstract access 

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.

Orkin C,  DeJesus E, Ramgopal M, Crofoot G, Ruane P, LaMarca A, Mills A, Vandercam B, de Wet J, Rockstroh J, Lazzarin A, Rijnders B, Podzamczer D, Thalme A, Stoeckle M, Porter D, Liu HC, Cheng A, Quirk E, SenGupta D, Cao H. Lancet HIV. 2017 Mar 1. pii: S2352-3018(17)30031-0. doi:10.1016/S2352-3018(17)30031-0. [Epub ahead of print]

Background: Tenofovir alafenamide, a tenofovir prodrug, results in 90% lower tenofovir plasma concentrations than does tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate.

Methods: In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per ml) on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 ml/min. Participants were randomly assigned(1:1) to receive a single-tablet regimen of either rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to remain on a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo, once daily for 96 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug and were on the tenofovir disoproxil fumarate regimen before screening were included in primary efficacy analyses. The primary endpoint was the proportion of participants with less than 50 copies per ml of plasma HIV-1 RNA at week 48 (by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with clinicaltrials.gov, number NCT01815736.

Findings: Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the tenofovir alafenamide group and 314 to the tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on tenofovir alafenamide and 294 (94%) of 313 on tenofovir disoproxil fumarate had maintained less than 50 copies per ml HIV-1 RNA (difference -0·3%, 95·001% CI-4·2 to 3·7), showing non-inferiority of tenofovir alafenamide to tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20(6%) of 316 participants had study-drug related adverse events in the tenofovir alafenamide group compared with 37 (12%) of 314 in the tenofovir disoproxil fumarate group; none of these were serious.

Interpretation: Switching to rilpivirine, emtricitabine, and tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection.

Abstract access 

Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.

DeJesus E, Ramgopal M, Crofoot G, Ruane P, LaMarca A, Mills A, Martorell CT, de Wet J, Stellbrink HJ, Molina JM, Post FA, Valero IP, Porter D, Liu Y, Cheng A, Quirk E, SenGupta D, Cao H. Lancet HIV. 2017 Mar 1. pii: S2352-3018(17)30032-2. doi:10.1016/S2352-3018(17)30032-2. [Epub ahead of print]

Background: Tenofovir alafenamide is a prodrug that reduces tenofovir plasma concentrations by 90% compared with tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine,and tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and tenofovir disoproxil fumarate.

Methods: In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on efavirenz, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned(1:1) to receive a single-tablet regimen of rilpivirine (25 mg), emtricitabine(200 mg), and tenofovir alafenamide (25 mg) or to continue a single-tablet regimen of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50copies per mL at week 48 (assessed by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT02345226.

Findings: Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and tenofovir alafenamide and 437 with efavirenz, emtricitabine, tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the tenofovir disoproxil fumarate regimen (difference -2·0%, 95·001% CI -5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group.

Interpretation: Switching to rilpivirine, emtricitabine, and tenofovir alafenamide from efavirenz, emtricitabine, and tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection.

Abstract access 

Incidence and risk factors for hypertension among HIV patients in rural Tanzania - A prospective cohort study.

Rodríguez-Arbolí E, Mwamelo K, Kalinjuma AV, Furrer H, Hatz C, Tanner M, Battegay M, Letang E; KIULARCO Study Group. PLoS One. 2017 Mar 8;12(3):e0172089. doi: 10.1371/journal.pone.0172089.eCollection 2017.

Introduction: Scarce data are available on the epidemiology of hypertension among HIV patients in rural sub-Saharan Africa. We explored the prevalence, incidence and risk factors for incident hypertension among patients who were enrolled in a rural HIV cohort in Tanzania.

Methods: Prospective longitudinal study including HIV patients enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2013 and 2015. Non-ART naïve subjects at baseline and pregnant women during follow-up were excluded from the analysis. Incident hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg on two consecutive visits. Cox proportional hazards models were used to assess the association of baseline characteristics and incident hypertension.

Results: Among 955 ART-naïve, eligible subjects, 111 (11.6%) were hypertensive at recruitment. Ten women were excluded due to pregnancy. The remaining 834 individuals contributed 7967 person-months to follow-up (median 231 days, IQR 119-421) and 80 (9.6%) of them developed hypertension during a median follow-up of 144 days from time of enrolment into the cohort [incidence rate 120.0 cases/1000 person-years, 95% confidence interval (CI) 97.2-150.0]. ART was started in 630 (75.5%) patients, with a median follow-up on ART of 7 months (IQR 4-14). Cox regression models identified age [adjusted hazard ratio (aHR) 1.34 per 10 years increase, 95% CI 1.07-1.68, p = 0.010], body mass index (aHR per 5 kg/m2 1.45, 95% CI 1.07-1.99, p = 0.018) and estimated glomerular filtration rate (aHR < 60 versus ≥ 60 ml/min/1.73 m2 3.79, 95% CI 1.60-8.99, p = 0.003) as independent risk factors for hypertension development.

Conclusions: The prevalence and incidence of hypertension were high in our cohort. Traditional cardiovascular risk factors predicted incident hypertension, but no association was observed with immunological or ART status. These data support the implementation of routine hypertension screening and integrated management into HIV programmes in rural sub-Saharan Africa.

Abstract  Full-text [free] access

Cigarette smoking is associated with high HIV viral load among adults presenting for antiretroviral therapy in Vietnam.

Pollack TM, Duong HT, Pham TT, Do CD, Colby D. PLoS One. 2017 Mar 7;12(3):e0173534. doi: 10.1371/journal.pone.0173534.eCollection 2017.

High HIV viral load (VL >100 000 cp/ml) is associated with increased HIV transmission risk, faster progression to AIDS, and reduced response to some antiretroviral regimens. To better understand factors associated with high VL, we examined characteristics of patients presenting for treatment in Hanoi, Vietnam. We examined baseline data from the Viral Load Monitoring in Vietnam Study, a randomized controlled trial of routine VL monitoring in a population starting antiretroviral therapy (ART) at a clinic in Hanoi. Patients with prior treatment failure or ART resistance were excluded. Characteristics examined included demographics, clinical and laboratory data, and substance use. Logistic regression was used to calculate crude and adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Out of 636 patients, 62.7% were male, 72.9% were ≥30 years old, and 28.3% had a history of drug injection. Median CD4 was 132cells/mm3, and 34.9% were clinical stage IV. Active cigarette smoking was reported by 36.3% with 14.0% smoking >10 cigarettes per day. Alcohol consumption was reported by 20.1% with 6.1% having ≥5 drinks per event. Overall 53.0% had a VL >100 000 cp/ml. Male gender, low body weight, low CD4 count, prior TB, and cigarette smoking were associated with high VL. Those who smoked 1-10 cigarettes per day were more likely to have high VL (aOR = 1.99, 95% CI = 1.15-3.45), while the smaller number of patients who smoked >10 cigarettes per day had a non-significant trend toward higher VL (aOR = 1.41, 95% CI = 0.75-2.66). Alcohol consumption was not significantly associated with high VL. Tobacco use is increasingly recognized as a contributor to premature morbidity and mortality among HIV-infected patients. In our study, cigarette smoking in the last 30 days was associated with a 1.5 to 2-fold higher odds of having an HIV VL >100 000 cp/ml among patients presenting for ART. These findings provide further evidence of the negative effects of tobacco use among HIV-infected patients.

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Predictors of eGFR progression, stabilisation or improvement after chronic renal impairment in HIV-positive individuals.

Ryom L, Mocroft A, Kirk O, Reiss P, Ross M, Smith C, Moranne O, Morlat P, Fux CA, Sabin C, Phillips A, Law M, Lundgren JD; D:A:D study group. AIDS. 2017 Mar 28. doi: 10.1097/QAD.0000000000001464. [Epub ahead of print]

Objectives: The objectives of this analysis were to investigate predictors of progression, stabilisation or improvement in eGFR after development of chronic renal impairment (CRI) in HIV-positive individuals.

Design: Prospective observational study.

Methods: D:A:D study participants progressing to CRI defined as confirmed, ≥ 3 months apart, eGFR ≤70  mL/min/1.73m were included in the analysis. The median of all eGFRs measured 24-36 months post-CRI was compared to the median eGFR defining CRI, and changes were grouped into: improvement (>+10 mL/min/1.73m), stabilisation (-10 to +10 mL/min/1.73m) and progression (<-10 mL/min/1.73m). Adjusted polynomial regression models assessed odds of better eGFR outcomes after CRI, assuming eGFR improvement is better than stabilisation which in turn is better than progression.

Results: Of 2006 individuals developing CRI, 21% subsequently improved eGFR, 67% stabilised and 12% progressed. Individuals remaining on TDF or boosted atazanavir (ATV/r) 24 months post-CRI had worse eGFR outcomes compared to those unexposed (TDF: 0.47 [0.35-0.63], ATV/r: 0.63 [0.48-0.82]). Individuals off TDF for 12-24 months (0.75 [0.50-1.13]) or off ATV/r for >12 months (1.17 [0.87-1.57]) had similar eGFR outcomes as those unexposed to these ARVs. Older age, hypertension, later date of CRI and diabetes were associated with worse eGFR outcomes.

Conclusion: Current TDF and ATV/r use after a diagnosis of CRI was associated with worse eGFR outcomes. In contrast, TDF and ATV/r discontinuation lead to similar longer-term eGFR outcomes as in those unexposed suggesting these drug-associated eGFR declines may be halted or reversed after their cessation.

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Comorbidity, HIV Treatment
Africa, Asia, Europe, Northern America, Oceania
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Phylogenetics - powerful new tools tied to ethical imperatives for key populations

Editor’s notes: There are now well over half a million HIV isolates that have been sequenced and the data stored in public accessible Genbank.  A systematic review by Hassan AS and colleagues of the methods used to define phylogenetic trees and clusters within them demonstrates the importance of using the correct criteria for the hypothesis being tested. Most articles use the pol sequence, since this is what is sequenced for drug resistance testing.  Most analyses have been done using a phylogenetic approach that uses a probability to assess the likelihood that isolates are clustered, and so depends on the cut-off value chosen.  For example, a well-studied outbreak of HIV among drug users in Finland is clearly linked to an earlier outbreak in Sweden, but because the Finnish isolates were collected later, they had already diverged somewhat from the Swedish ones.  If the threshold was set too high, they would not be recognized to be part of the same outbreak.  However for active transmission chains, a high threshold is needed to avoid falsely linking isolates.  There is no consensus on what methods to use, so caution is needed when comparing different studies.

Mark Wainberg, Professor of Medicine and of Microbiology at McGill University and a giant of Canadian HIV science, passed away this month.  So, as a tribute to his work, we have chosen a study from the McGill AIDS Centre by Brenner BG and colleagues.  The team used phylogenetic analysis to classify pre-treatment HIV isolates from 3901 men who have sex with men in Quebec according to the likelihood of being an acute or recent infection and the likelihood of clustering with other isolates.  Over the period from 2002-2015, a larger and larger proportion of the infections in this population could be linked to larger clusters, particularly involving younger men and men with recent infection, many of whom did not know their HIV status.  At least 40% of the onward spread of the epidemic in Quebec can be ascribed to just thirty clusters, varying in size from 20–140 individuals.

Using phylogenetics to understand transmission patterns requires careful attention to ethics, confidentiality and stigmatization.  A study in South Korea by Ahn MY and colleagues aimed to define the risk factors for clustering within clusters among 143 people living with HIV in four cities.  In eight out of the nine clusters identified participants did not report the same risk factors. Clusters were small, eight pairs and one quartet.  In the two tightest clusters, where the isolates were indistinguishable on the sequences examined, one man stated that he had sex with women, but the paired isolate came from another man and in the other pair, both men chose not to disclose their risk factors.  With small studies where information can sometimes be inferred even when not disclosed, it is perhaps not surprising that more than half the participants chose not to report their risk factors.

Other phylogenetic studies this month have explored the evolution of HIV recombination and the spread of different clades in communities in North-Eastern Brazil [Delatorre E et al.] and China.  In the North-Eastern states of Brazil, 72% of HIV isolates were subtype B, but rare subtypes such as D (1%) and CRF02_AG (1%) appear to be spreading within the population rather than being introduced from outside. In China studies from Sichuan [Wang Y et al.], Yunnan [Li Y and colleagues] and Zhejiang [Wang H et al.] have shown new recombinant forms of HIV with elements that suggest that viruses from different countries in the region have combined.  The widening diversity of HIV brings challenges for vaccine development, and potentially for HIV assays, such as those for recent infection that may differ in their sensitivity and specificity between different sub-types.  Understanding the migration of people and their viruses could be useful for providing better services, but careful attention to messaging will be needed to prevent such data from being used to discriminate further against migrants.

The final phylogenetic paper this month also comes from China, where Hao M and colleagues reported a study of students living with HIV in Beijing. The study demonstrated that transmitted drug resistance is still low in this setting, with just 0.8% of 237 students having virus that was resistant to non-nucleoside reverse transcriptase inhibitors that form part of the backbone of first line treatment in China.  A further 1.3% has resistance to protease inhibitors that are used in second line treatment.

Defining HIV-1 transmission clusters based on sequence data: a systematic review and perspectives.

Hassan AS, Pybus OG, Sanders EJ, Albert J, Esbjörnsson J. AIDS. 2017 Mar 28. doi: 10.1097/QAD.0000000000001470. [Epub ahead of print]

Understanding HIV-1 transmission dynamics is relevant to both screening and intervention strategies of HIV-1 infection. Commonly, HIV-1 transmission chains are determined based on sequence similarity assessed either directly from a sequence alignment or by inferring a phylogenetic tree. This review is aimed at both nonexperts interested in understanding and interpreting studies of HIV-1transmission, and experts interested in finding the most appropriate cluster definition for a specific dataset and research question. We start by introducing the concepts and methodologies of how HIV-1 transmission clusters usually have been defined. We then present the results of a systematic review of 105 HIV-1 molecular epidemiology studies summarizing the most popular methods and definitions in the literature. Finally, we offer our perspectives on how HIV-1 transmission clusters can be defined and provide some guidance based on examples from real life datasets.

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Large cluster outbreaks sustain the HIV epidemic among MSM in Quebec.

Brenner BG, Ibanescu RI, Hardy I, Stephens D, Otis J, Moodie E, Grossman Z,Vandamme AM, Roger M, Wainberg MA; and the Montreal PHI, SPOT cohorts. AIDS. 2017 Mar 13;31(5):707-717. doi: 10.1097/QAD.0000000000001383.

Objective: HIV-1 epidemics among MSM remain unchecked despite advances in treatment and prevention paradigms. This study combined viral phylogenetic and behavioural risk data to better understand underlying factors governing the temporal growth of the HIV epidemic among MSM in Quebec (2002-2015).

Methods: Phylogenetic analysis of pol sequences was used to deduce HIV-1transmission dynamics (cluster size, size distribution and growth rate) in first genotypes of treatment-naïve MSM (2002-2015, n = 3901). Low sequence diversity of first genotypes (0-0.44% mixed base calls) was used as an indication of early-stage infection. Behavioural risk data were obtained from the Montreal rapid testing site and primary HIV-1-infection cohorts.

Results: Phylogenetic analyses uncovered high proportion of clustering of new MSM infections. Overall, 27, 45, 48, 53 and 57% of first genotypes within one (singleton, n = 1359), 2-4 (n = 692), 5-9 (n = 367), 10-19 (n = 405) and 20+ (n = 1277) cluster size groups were early infections (<0.44% diversity). Thirty viruses within large 20+ clusters disproportionately fuelled the epidemic, representing 13, 25 and 42% of infections, first genotyped in 2004-2007 (n = 1314), 2008-2011 (n = 1356) and 2012-2015 (n = 1033), respectively. Of note, 35, 21 and 14% of MSM belonging to 20+, 2-19 and one (singleton) cluster groups were under 30 years of age, respectively. Half of persons seen at the rapid testing site (2009-2011, n = 1781) were untested in the prior year. Poor testing propensity was associated with fewer reported partnerships.

Conclusion: Addressing the heterogeneity in transmission dynamics among HIV-1-infected MSM populations may help guide testing, treatment and prevention strategies.

Abstract access 

HIV-1 transmission networks across South Korea.

Ahn MY, Wertheim JO, Kim WJ, Kim SW, Lee JS, Ann HW, Jeon Y, Ahn JY, Song JE, Oh DH, Kim YC, Kim EJ), Jung IY, Kim MH, Jeong W, Jeong SJ, Ku NS, Kim JM, Smith DM, Choi JY. AIDS Res Hum Retroviruses. 2017 Mar 27. doi: 10.1089/aid.2016.0212. [Epub ahead of print]

Molecular epidemiology can help clarify the properties and dynamics of HIV-1 transmission networks in both global and regional scales. We studied 143 HIV-1-infected individuals recruited from four medical centers of three cities in South Korea between April 2013 and May 2014. HIV-1 env V3 sequence data were generated (337-793 bp) and analyzed using a pairwise distance-based clustering approach to infer putative transmission networks. Participants whose viruses were ≤2.0% divergent according to Tamura-Nei 93 genetic distance were defined as clustering. We collected demographic, risk, and clinical data and analyzed these data in relation to clustering. Among 143 participants, we identified nine putative transmission clusters of different sizes (range 2-4 participants). The reported risk factor of participants were concordant in only one network involving two participants, that is, both individuals reported homosexual sex as their risk factor. The participants in the other eight networks did not report concordant risk factors, although they were phylogenetically linked. About half of the participants refused to report their risk factor. Overall, molecular epidemiology provides more information to understand local transmission networks and the risks associated with these networks.

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HIV-1 Genetic diversity in northeastern Brazil: high prevalence of non-B subtypes.

Delatorre E, Couto-Fernandez JC, Bello G.AIDS Res Hum Retroviruses. 2017 Mar 22. doi: 10.1089/AID.2017.0045. [Epub ahead of print]

The Northeastern Brazilian region has experienced a constant increase in the number of newly reported AIDS cases over the last decade, but the genetic diversity of HIV-1 strains currently disseminated in this region remains poorly explored. HIV-1 pol sequences were obtained from 140 patients followed at outpatient clinics from four Northeastern Brazilian states (Alagoas, Bahia, Ceará and Piauí) between 2014 and 2015. Subtype B was the most prevalent HIV-1 clade (72%) detected in the Northeastern region, followed by subtypes F1 (6%), C (5%) and D (1%). The remaining strains (16%) displayed a recombinant structure and were classified as: BF1 (11%), BC (4%), BCF1 (1%) and CRF02_AG-like (1%). The 20 HIV-1 BF1 and BC recombinant sequences detected were distributed among 11 lineages classified as: CRF28/29_BF-like (n = 5), CRF39_BF-like (n = 1), URFs_BF (n = 9) and URFs_BC (n = 5). Non-B subtypes were detected in all Northeastern Brazilian states, but with variable prevalence, ranging from 16% in Ceará to 55% in Alagoas. Phylogenetics analyses support that subtype D and CRF02_AG strains detected in the Northeastern region resulted from the expansion of autochthonous transmission networks, rather than from exogenous introductions from other countries. These results reveal that HIV-1 epidemic spreading in the Northeastern Brazilian region is comprised by multiple subtypes and recombinant strains and that the molecular epidemiologic pattern in this Brazilian region is much more complex than originally estimated.

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Identification of a novel HIV type 1 CRF01_AE/B'/C recombinant isolate in Sichuan, China.

Wang Y, Kong D, Xu W, Li F, Liang S, Feng Y, Zhang F, Shao Y, Ma L. AIDS Res Hum Retroviruses. 2017 Mar 13. doi: 10.1089/aid.2017.0002. [Epub ahead of print]

We report in this study a novel HIV-1 unique recombinant virus (XC2014EU01) isolated from an HIV-positive man who infected through heterosexual sex in Sichuan, China. The near full-length genome analyses showed that XC2014EU01 harbored one subtype B segment in pol region and two subtype C segments in gag-pol region in a CRF01_AE backbone. The unique mosaic structure was distinctly different from the other CRF01_AE/B'/C recombinant forms reported. Phylogenetic tree analyses revealed that the subtype B region originated from a Thailand subtype B' lineage, the subtype C regions were from an India C lineage, and the backbone was from CRF01_AE. XC2014EU01 was still identified as CCR5-tropic, and plasma of XC2014EU01 infected person had the media neutralizing activity. The emergence of XC2014EU01 may increase the complexity of the HIV-1 epidemic among high-risk populations and the difficulty of vaccine research and development.

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Identification of a novel HIV type 1 circulating recombinant form (CRF86_BC) among heterosexuals in Yunnan, China.

Li Y, Miao J, Miao Z, Song Y, Wen M, Zhang Y, Guo S, Zhao Y, Feng Y, Xia X. AIDS Res Hum Retroviruses. 2017 Mar;33(3):279-283. doi: 10.1089/AID.2016.0188. Epub 2016 Oct 18.

In recent years, multiple circulating recombinant forms (CRFs) and unique recombinant forms of human immunodeficiency virus type 1 (HIV-1) have been described in Yunnan, China. Here, we identified a novel HIV-1 CRF (CRF86_BC) isolated from three heterosexuals with no obvious epidemiologic linkage in western Yunnan (Baoshan prefecture) in China. CRF86_BC had a subtype C backbone with four subtype B fragments inserted into the pol, vpr, vpu, env, and nef gene regions, respectively. Furthermore, subregion tree analysis revealed that subtype C backbone originated from an Indian C lineage and subtype B segment inserted was from a Thai B lineage. They are different from previously documented B/C forms in its distinct backbone, inserted fragment size, and break points. This highlighted the importance of continual monitoring of genetic diversity and complexity of HIV-1 strains in this region.

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Near full-length genomic characterization of a novel HIV-1 unique recombinant (CRF55_01B/CRF07_BC) from a Malaysian immigrant worker in Zhejiang, China.

Wang H, Luo P, Zhu H, Wang N, Hu J, Mo Q, Yang Z, Feng Y. AIDS Res Hum Retroviruses. 2017 Mar;33(3):275-278.doi: 10.1089/AID.2016.0100. Epub 2016 Aug 17.

Recombinant forms contribute substantially to the genetic diversity of human immunodeficiency virus type 1 (HIV-1). Here we report a novel HIV-1 recombinant detected from a comprehensive HIV-1 molecular epidemiologic study among cross-border populations in China. Near full-length genome (NFLG) phylogenetic analysis showed that the novel HIV-1 recombinant ZJCIQ15005, which was isolated from a Malaysian immigrant worker in Zhejiang, China, clustered with CRF55_01B reference sequences but set up a distinct branch. Recombinant analysis showed that the NFLG of ZJCIQ15005 composed of CRF55_01B (as the backbone) and CRF07_BC,with 12 recombinant break points observed in the pol, vif, vpr, tat, rev, env,nef, and 3'LTR regions. This is the first detection of a novel HIV-1 recombinant (CRF55_01B/CRF07_BC) in immigrant workers in China. The emergence of this recombinant may increase the complexity of the HIV-1 epidemic in China and suggests the importance of continuous surveillance of the dynamic changes of HIV-1.

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Low rates of transmitted drug resistances among treatment-naive HIV-1 infected students in Beijing, China.

Hao M, Wang J, Xin R, Li X, Hao Y, Chen J, Ye J, Wang Y, He X, Huang C, Lu H. AIDS Res Hum Retroviruses. 2017 Mar 22. doi: 10.1089/AID.2017.0053. [Epub ahead of print]

Beijing has seen a rising epidemic of HIV among students. However, little information was known about the molecular epidemiologic data among HIV-infected students. In this study, the diversity and the prevalence of TDR in pol sequences deriving from 237 HIV-infected students were analyzed. TDR mutations were found in 5 MSM among students. The overall prevalence of TDR in students was 2.1%, comprised of 1.3% to protease inhibitors and 0.8 % to non-nucleoside reverse transcriptase inhibitors. Our finding indicates a low-level prevalence of TDR mutations among students in Beijing.

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Asia, Latin America, Northern America
Brazil, Canada, China, Republic of Korea
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Improving programmes: a thematic synthesis of qualitative studies of treatment adherence programmes

Barriers and facilitators of interventions for improving antiretroviral therapy adherence: a systematic review of global qualitative evidence.

Ma Q, Tso LS, Rich ZC, Hall BJ, Beanland R, Li H, Lackey M, Hu F, Cai W, Doherty M, Tucker JD. J Int AIDS Soc. 2016 Oct 17;19(1):21166. doi: 10.7448/IAS.19.1.21166. eCollection 2016.

Introduction: Qualitative research on antiretroviral therapy (ART) adherence interventions can provide a deeper understanding of intervention facilitators and barriers. This systematic review aims to synthesize qualitative evidence of interventions for improving ART adherence and to inform patient-centred policymaking.

Methods: We searched 19 databases to identify studies presenting primary qualitative data on the experiences, attitudes and acceptability of interventions to improve ART adherence among PLHIV and treatment providers. We used thematic synthesis to synthesize qualitative evidence and the CERQual (Confidence in the Evidence from Reviews of Qualitative Research) approach to assess the confidence of review findings.

Results: Of 2982 references identified, a total of 31 studies from 17 countries were included. Twelve studies were conducted in high-income countries, 13 in middle-income countries and six in low-income countries. Study populations focused on adults living with HIV (21 studies, n=1025), children living with HIV (two studies, n=46), adolescents living with HIV (four studies, n=70) and pregnant women living with HIV (one study, n=79). Twenty-three studies examined PLHIV perspectives and 13 studies examined healthcare provider perspectives. We identified six themes related to types of interventions, including task shifting, education, mobile phone text messaging, directly observed therapy, medical professional outreach and complex interventions. We also identified five cross-cutting themes, including strengthening social relationships, ensuring confidentiality, empowerment of PLHIV, compensation and integrating religious beliefs into interventions. Our qualitative evidence suggests that strengthening PLHIV social relationships, PLHIV empowerment and developing culturally appropriate interventions may facilitate adherence interventions. Our study indicates that potential barriers are inadequate training and compensation for lay health workers and inadvertent disclosure of serostatus by participating in the intervention.

Conclusions: Our study evaluated adherence interventions based on qualitative data from PLHIV and health providers. The study underlines the importance of incorporating social and cultural factors into the design and implementation of interventions. Further qualitative research is needed to evaluate ART adherence interventions.

Abstract  Full-text [free] access 

Editor’s notes: This is a review of studies using qualitative methods to explore the experiences of people living with HIV and healthcare providers involved in programmes to support antiretroviral treatment adherence. The thematic synthesis is presented in two ways. First, the reviewed studies are categorised by types of adherence programmes, such as task shifting, education, or directly observed therapy. Secondly, the authors present themes that are common across all reviewed studies. These include: the benefits and challenges of employing lay healthcare workers; the need to maintain confidentiality in adherence programmes; the benefits of supporting empowerment and social relationships for people living with HIV; and the need for culturally appropriate information and practice. Overall the review illustrates that adherence programmes can have more impact if they address confidentiality, strengthen social ties among people living with HIV and their communities; provide adequate compensation and training for lay healthcare workers; and sensitively reflect local social, cultural and religious norms and beliefs. 

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