Articles tagged as "Latin America"

Despite better access to HIV treatment we need stronger evidence based guidance on treating people with serious complications of advanced HIV infection

Editor’s notes: The emphasis for scaling up HIV treatment usually focuses on outpatient and primary care clinics with increasing decentralization to the community.  It is therefore sobering to see the results of a randomized trial conducted at a national referral hospital in Zambia.  Andrews and colleagues report on 209 adults admitted to hospital with sepsis and hypotension, a combination referred to as septic shock.  Several important points emerge.  Almost 90% of patients admitted with this serious condition were HIV-positive.  Most had only been diagnosed with HIV infection in the last three months, and approximately half were taking ART.  The median CD4 count was only 70 cells per microlitre. Almost half had a history of having tuberculosis and one quarter were currently on anti-tuberculosis treatment at the time of admission to hospital. Most were also anaemic, with an average haemoglobin of 7.8 g/dl. Mortality from septic shock has been falling in Europe and the United States of America largely due to more intensive management of intravenous fluids and blood pressure.  The focus has been on strict protocols to ensure that all patients get the best treatment. However, there has been debate about the best approach to take when less sophisticated monitoring and supportive technology such as artificial ventilation is not available. In this Zambian tertiary hospital setting, only one patient was able to be managed in the intensive care unit due to resource constraints.  Patients were randomized to receive a protocolized intensive fluid and blood pressure resuscitation or to receive the more standard care with the responsible physicians making the decisions.  The death rate from this severe condition was very high.  85 of the 209 patients randomized died.  However, despite receiving more intravenous fluids, more blood transfusions and more drugs to raise blood pressure, the outcomes were worse in the group treated according to the protocol with 48% mortality compared to 33% in the standard care arm.  As always, the lesson is that many of these deaths could have been avoided if we were able to diagnose, link and treat people living with HIV much earlier in the course of their infection.  However, there is also an important caution that treatments that make good sense and seem the best course of action may in fact make the situation worse, even if the same treatments have been shown in other contexts to be beneficial.  Such information will only come from randomized trials, and the authors should be congratulated for being bold enough to conduct a high-quality study that should make us reflect on our preconceptions about how best to treat seriously ill patients in resource poor settings.

Andrade and colleagues have reviewed the literature in order to determine the best approach to treating critically unwell people living with HIV who are admitted to intensive care units.  They examined whether starting ARVs while the person was already critically ill was associated with better outcomes.  Patients in intensive care may already have many different medicines, as well as altered metabolism.  In addition, ARVs can provoke immune reconstitution inflammatory syndromes that have been shown to make outcomes worse in some serious conditions such as cryptococcal meningitis.  On the other hand, the evidence from patients with tuberculosis is clear – starting ARVs as soon as possible is associated with better outcomes.  In this review and meta-analysis, there was a clear short-term advantage to starting ARVs while the patient was still in intensive care.  The data were not sufficient to tell whether the longer-term outcome as also improved by the earlier start of ART.  One limitation is that all the studies reviewed were observational, and the decision to start ARVs was not randomized, so that it is plausible that clinicians may have started ARVs more willingly in those patients who were most likely to survive.  Nonetheless, in the absence of randomized trials, this study makes a strong case for starting ARVs promptly even in the sickest patients.

Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial.

Andrews B, Semler MW, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, Mabula C, Bwalya M, Bernard GR. JAMA. 2017 Oct 3;318(13):1233-1240. doi: 10.1001/jama.2017.10913.

Importance: The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown.

Objective: To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care.

Design, setting, and participants: Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013.

Interventions: Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management.

Main outcomes and measures: The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors.

Results: Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001).

Conclusions and relevance: Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations.

Abstract access

Highly active antiretroviral therapy for critically ill HIV patients: a systematic review and meta-analysis.

Andrade HB, Shinotsuka CR, da Silva IRF, Donini CS, Yeh Li H, de Carvalho FB, Americano do Brasil PEA, Bozza FA, Miguel Japiassu A. PLoS One. 2017 Oct 24;12(10):e0186968. doi:10.1371/journal.pone.0186968. eCollection 2017

Introduction: It is unclear whether the treatment of an HIV infection with highly active antiretroviral therapy (HAART) affects intensive care unit (ICU) outcomes. In this paper, we report the results of a systematic review and meta-analysis performed to summarize the effects of HAART on the prognosis of critically ill HIV positive patients.

Materials and methods: A bibliographic search was performed in 3 databases (PubMed, Web of Science and Scopus) to identify articles that investigated the use of HAART during ICU admissions for short- and long-term mortality or survival. Eligible articles were selected in a staged process and were independently assessed by two investigators. The methodological quality of the selected articles was evaluated using the Methodological Index for Non-Randomized Studies (MINORS) tool.

Results: Twelve articles met the systematic review inclusion criteria and examined short-term mortality. Six of them also examined long-term mortality (≥90 days) after ICU discharge. The short-term mortality meta-analysis showed a significant beneficial effect of initiating or maintaining HAART during the ICU stay (random effects odds ratio 0.53, p = 0.02). The data analysis of long-term outcomes also suggested a reduced mortality when HAART was used, but the effect of HAART on long-term mortality of HIV positive critically ill patients remains uncertain.

Conclusions: This meta-analysis suggests improved survival rates for HIV positive patients who were treated with HAART during their ICU admission.

Abstract  Full-text [free] access

  • share
0 comments.

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.

Abstract  Full-text [free] access

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).

Abstract  Full-text [free] access

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.

Abstract  Full-text [free] access

  • share
0 comments.

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.

Abstract access

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.

Abstract  Full-text [free] access

  • share
0 comments.

HIV testing and the HIV epidemic –vitally important to prevent HIV becoming endemic

Editor’s notes: Epidemics refer to situations where the number of infections rises (and subsequently falls) more quickly than might be expected compared to a disease that is endemic.  Endemic implies a stable situation, with natural fluctuations in the number of cases.  Medley and Vassal have written a provocative article in Science that considers how differently individuals, communities and society react to epidemic rather than endemic diseases.  They choose to call HIV in 2017 endemic, which carries a serious risk. As the authors state, “The contained public response, and the concurrent shift of responsibility to individuals to protect themselves from risk, means that endemic disease embeds itself further, as those at risk are often the very same people who do not have the private resources to avoid risk or access treatment.”  There are in fact multiple separate epidemics of HIV in different regions and in different populations.  Some are rising and some are falling. The latest UNAIDS’ report emphasizes the heterogeneity of HIV infections in the world.  New HIV infections have fallen by 29% since 2010 in East and Southern Africa, the region with the highest rates.  On the other hand, new HIV infections have risen by an alarming 60% in Eastern Europe and Central Asia over the same period, albeit from a much lower baseline.  There is widespread political consensus to pursue the UN agenda endorsed at the High Level Meeting on Ending AIDS in New York last year.  Let’s not throw in the towel too soon!

HIV testing services remain central to the HIV strategy and, as usual, this month there are several important papers on aspects of HIV testing, many of which illustrate challenges that need to be overcome.

There are several reasons to encourage people living with HIV to know their status.  First and foremost, we know that the earlier treatment is started in the course of HIV, the better the outlook for the individual.  People who start treatment become much less likely to transmit HIV infection to sexual partners. People who know their HIV status are also able to make informed decisions about their lives and their partnerships.  A study this month by Escudero et al. from New York City used agent-based modelling to understand the testing and care continuum for people who inject drugs. Their results remind us of the key role of HIV testing.  They estimated that 53% of the HIV transmission events from people who inject drugs arose from people who did not know their status, and a further 37% from people who had not been started ART.  In other words, they estimate that only 10-11% of infections from people who inject drugs could be prevented by improving quality of care for people on treatment.  The need to find effective ways to encourage people at risk to know their status and start treatment is stark.

Guanzhou is one of the largest cities in China, with a high population of migrants both national and international.  It is among the most prosperous regions of Guangdong province and has the highest rates of HIV.   Chen et al. added some HIV testing related questions to a wider population based health survey in two districts and showed that approximately a quarter of adults had previously been tested for HIV.  HIV testing was almost all provided through free government facilities or blood transfusion centres.  Despite early steps to make HIV self-testing more available, none of the 666 participants who answered the relevant questions in the survey had used a self-test.  Distance from an HIV testing site was a key determinant of the likelihood of getting tested.  It was not clear that people who might be at higher risk were more likely to be tested, although the numbers and sampling focused on the general population rather than people at special risk.

Wang et al. explored the different HIV test kits used in the first line screening in Xi’an.  In line with Chinese guidelines, but not in line with WHO guidance on HIV testing algorithms for low prevalence settings, they used third- or fourth-generation rapid tests and repeated the positive tests.  WHO’s algorithm for low prevalence settings includes three different rapid tests based on different antigens.   Among 665 people found to be positive on rapid tests, only 559 were confirmed to be HIV-positive by Western blotting.  Subsequent follow up with additional Western blots showed that two of the individuals in whom the first Western blot was indeterminate were seroconverting but the other 104 were HIV-negative and had had false-positive results on the original rapid tests.  False positives were more likely with the fourth-generation test (22% of positive tests) compared to the various third-generation tests used (9-11% of positive tests).  Fourth-generation assays are known to be more sensitive, detecting people with HIV around a week or two earlier in the window period than third-generation assays.  However, the authors point out that in low prevalence settings like Xi’an, the known lack of specificity of fourth-generation assays means that they may not provide sufficient advantages to be used as the first line test.  Overall, the paper emphasizes the importance of using clearly defined algorithms.  The WHO algorithms no longer use Western blots, but do recommend using multiple tests based on different antigens for testing people at low risk of infection, and at least two different tests with different antigens for testing people at high risk of infection.  Everyone should have additional confirmatory tests done prior to starting ART.

Harbertson et al. also focused on the accuracy of rapid diagnostic tests.  They screened samples from 459 military personnel in seven African countries who had reported that they were HIV-positive.  Using the WHO algorithm, they compared the results of quality assured HIV testing to the self-reported HIV status of the participants.  They found that, in different country surveys, between three and 91% of people who said that they were living with HIV were in fact HIV-negative.  The authors point out that several studies have demonstrated the importance of following the WHO guidance, and that the positive predictive value of a test (or algorithm) will always fall as the overall prevalence falls.  They discuss possible limitations such as misunderstanding the question or the terminology used, but discount these possibilities as causing many of the false-positive reports, particularly given the highly variable results across different countries.  There was a strong association between the likelihood of a false positive report and lower education level. People whose understanding of HIV was less good were also more likely to report themselves to be positive falsely.  Overall, the authors assume that quality of testing services needs to be an important priority, while not discounting the challenges of using self-reports to collect information about HIV status.

As more and more people chose to know their HIV status, it may be possible to use routine data from the health service to track the epidemiology of HIV, rather than to use special surveys. Traditionally surveys of antenatal mothers have been used to monitor trends in the HIV epidemic over time.  With the widespread adoption of routine testing for mothers, a large proportion of women have an HIV test.  However, the assays used vary.  For surveillance purposes, samples are often stored and transported as dried blood spots and assays are run in batches using automated ELISA technology.  Routine testing (as discussed above) is often done using an algorithm based on a number of different rapid tests.   Pereira et al. have explored the differences between these approaches among almost 40 000 Brazilian mothers who participated in the antenatal surveillance exercise.  They interviewed mothers and linked their routine ANC results to the surveillance database.  Overall the prevalence of HIV among expectant mothers in Brazil was similar whichever approach was used (0.36% or 0.38%).  However, there were interesting differences.  The performance accuracy in those found positive in the surveillance exercise (which was taken as the gold standard) was only 84% overall and varied between regions from 43% to 100%.  So these 14 false negative results among the 88 individuals who were truly positive were compensated for in the overall prevalence estimates by a similar number (18) of false positive results among around 30 000 individuals who were truly negative. This highlights the challenges of providing accurate results to people in low prevalence settings. The 13% of mothers who slipped through the routine services and were not tested or refused to be tested were significantly more likely to be HIV-positive (0.56%), reinforcing the potential biases involved.  Finding 90% of people living with HIV will require considerable attention to the detail and the quality of HIV testing services.

Adolescents are often a population left behind, and regular reports show that adolescents living with HIV are less likely to know their status or to be on treatment or virally supressed.  Simms et al. used provider initiated testing and counselling (PITC) in primary care clinics in Harare, Zimbabwe.  For two years, the research team supported the routine offer of HIV testing to all six to 15 year olds presenting to seven clinics in a well-defined area of Harare.  The authors then conducted a population-based survey to find out how many eight to 17 year olds (who had had two years of exposure to the intervention) were aware of their status. 141 (2.6%) were living with HIV and more than one-third of these were undiagnosed.  Some had rarely been to the clinic, and others had been taken to the clinic by a guardian who was unable to consent to HIV testing on behalf of the child or the child’s parents.  Others had slipped through the PITC net, possibly because, as Lightfoot et al. in an accompanying comment suggest, providers still find it hard to offer HIV tests to everyone, as they assume that people living with HIV will not appear healthy.  This fits with the researchers’ findings that adolescents living with HIV who were currently healthy, had no skin or other problems and had parents who were alive were less likely to be diagnosed.  Both papers suggest that community based testing is needed to find adolescents. However, this also raises challenges in settings with lower prevalence than the high-density suburbs of Harare chosen for this project.  As prevalence falls lower than the 2.6% observed, a huge testing effort is needed, with attendant costs, but also (as explored above) with the risks of inaccurate results and of the very people that we want to find most, not being around for testing at the right moment. 

 

When an emerging disease becomes endemic.

Medley GF, Vassall A. Science. 2017 Jul 14;357(6347):156-158. doi: 10.1126/science.aam8333.

Epidemics, such as HIV in the early 1980s and Ebola in 2014, inspire decisive government investment and action, and individual and societal concern, sometimes bordering on panic. By contrast, endemic diseases, such as HIV in 2017 and tuberculosis, struggle to maintain the same attention. For many, the paradox is that endemic disease, in its totality, continues to impose a far higher public health burden than epidemic disease. Overall, the swift political response to epidemics has resulted in success. It has proven possible to eradicate epidemic diseases, often without the availability of vaccines and other biomedical technologies. In recent times, only HIV has made the transition from epidemic to endemic, but diseases that have existed for centuries continue to cause most of the infectious disease burden.

Abstract access

 

The risk of HIV transmission at each step of the HIV care continuum among people who inject drugs: a modeling study.

Escudero DJ, Lurie MN, Mayer KH, King M, Galea S, Friedman SR, Marshall BL. BMC Public Health. 2017 Jul 25;17(1):614. doi: 10.1186/s12889-017-4528-9.

Background: People who inject drugs (PWID) are at continued risk for HIV in the U.S., and experience disparities across the HIV care continuum compared to other high-risk groups. Estimates of the risk of HIV transmission at each stage of the care continuum may assist in identifying public health priorities for averting incident infections among PWID, in addition to transmissions to sexual partners of PWID.

Methods: We created an agent-based model simulating HIV transmission and the HIV care continuum for PWID in New York City (NYC) in 2012. To account for sexual transmission arising from PWID to non-PWID, the simulation included the entire adult NYC population. Using surveillance data and estimates from the National HIV Behavioral Surveillance system, we simulated a dynamic sexual and injecting network. We estimated the proportion of HIV transmission events attributable to PWID in the following categories, those: without an HIV diagnosis ('Undiagnosed'); diagnosed but not on antiretroviral therapy (ART) ('Diagnosed - not on ART'); those who initiated ART but were not virally suppressed ('Unsuppressed'); and, those who achieved viral suppression ('Suppressed').

Results: We estimated HIV incidence among PWID to be 113 per 100 000 person-years in 2012, with an overall incidence rate for the entire adult NYC population of 33 per 100 000 person-years. Despite accounting for only 33% of the HIV-infected PWID population, the Undiagnosed were associated with 52.6% (95% simulation interval [95% SI]: 47.1-57.0%) of total transmission events. The Diagnosed - not on ART population contributed the second-largest proportion of HIV transmissions, with 36.6% (95% SI: 32.2-41.5%). The Unsuppressed population contributed 8.7% (95% SI: 5.6-11.8%), and Suppressed 2.1% (95% SI: 1.1-3.9%), relatively little of overall transmission.

Conclusion: Among PWID in NYC, more than half (53%) of transmissions were from those who were unaware of their infection status and more than 36% were due to PWID who knew their status, but were not on treatment. Our results indicate the importance of early diagnosis and interventions to engage diagnosed PWID on treatment to further suppress population-level HIV transmission. Future HIV prevention research should focus on the elimination of identified and potential barriers to the testing, diagnosis, and retention of PWID on HIV treatment.

Abstract  Full-text [free] access

 

Is there a relationship between geographic distance and uptake of HIV testing services? A representative population-based study of Chinese adults in Guangzhou, China.

Chen W, Zhou F, Hall BJ, Tucker JD, Latkin C, Renzaho AMN, Ling L. PLoS One. 2017 Jul 20;12(7):e0180801. doi: 10.1371/journal.pone.0180801. eCollection 2017.

Achieving high coverage of HIV testing services is critical in many health systems, especially where HIV testing services remain centralized and inconvenient for many. As a result, planning the optimal spatial distribution of HIV testing sites is increasingly important. We aimed to assess the relationship between geographic distance and uptake of HIV testing services among the general population in Guangzhou, China. Utilizing spatial epidemiological methods and stratified household random sampling, we studied 666 adults aged 18-59. Computer-assisted interviews assessed self-reported HIV testing history. Spatial scan statistic assessed the clustering of participants who have ever been tested for HIV, and two-level logistic regression models assessed the association between uptake of HIV testing and the mean driving distance from the participant's residence to all HIV testing sites in the research sites. The percentage of participants who have ever been tested for HIV was 25.2% (168/666, 95%CI: 21.9%, 28.5%), and the majority (82.7%) of participants tested for HIV in Centres for Disease Control and Prevention, public hospitals or STIs clinics. None reported using self-testing. Spatial clustering analyses found a hotspot included 48 participants who have ever been tested for HIV and 25.8 expected cases (Rate Ratio = 1.86, P = 0.002). Adjusted two-level logistic regression found an inverse relationship between geographic distance (kilometers) and ever being tested for HIV (aOR = 0.90, 95%CI: 0.84, 0.96). Married or cohabiting participants (aOR = 2.14, 95%CI: 1.09, 4.20) and those with greater social support (aOR = 1.04, 95%CI: 1.01, 1.07) were more likely to be tested for HIV. Our findings underscore the importance of considering the geographical distribution of HIV testing sites to increase testing. In addition, expanding HIV testing coverage by introducing non-facility based HIV testing services and self-testing might be useful to achieve the goal that 90% of people living with HIV knowing their HIV status by the year 2020.

Abstract  Full-text [free] access

 

The characteristics of screening and confirmatory test results for HIV in Xi'an, China.

Wang L, Zhou KH, Zhao HP, Wang JH, Zheng HC, Yu Y, Chen W. PLoS One. 2017 Jul 7;12(7):e0180071. doi: 10.1371/journal.pone.0180071. eCollection 2017.

Objectives: Individuals with recent or acute HIV infection are more infectious than those with established infection. Our objective was to analyze the characteristics of detection among HIV infections in Xi'an.

Methods: A 4th-generation kit (Architect HIV Ag/Ab Combo) and three 3rd-generationEIA kits (WanTai, XinChuang and Livzon) were used for HIV screening. Overall, 665 individuals were identified as positive and were tested by western blotting (WB). The characteristics of the screening and confirmatory tests were analyzed, including the band patterns, the early detection performance and the false-positive rates.

Results: In total, 561 of the 665 patients were confirmed as having HIV-1 infection, and no HIV-2 specific band was observed. Among these 561 WB-positive cases, reactivity to greater than or equal to 9 antigens was the most commonly observed pattern (83.18%), and the absence of reactivity to p17, p31 and gp41 was detected in 6.44%, 5.9% and 2.86% of the cases, respectively. Two cases were positive by the 4th-generation assay but negative by the 3rd-generation assay for HIV screening and had seroconversion. The false-positive rate of the Architect HIV Ag/Ab Combo (22.01%) was significantly higher than those of WanTai (9.88%), XinChuang (10.87%) and Livzon (8.93%), p<0.05

Conclusion: HIV infection in Xi'an is mainly caused by HIV-1, and individuals are rarely identified at the early phase. Although the false-positive rate of the 4th-generation assay was higher than that of the 3rd-generation assay, it is still recommended for use as the initial HIV screening test for high-risk individuals. In Xi'an, a 3rd-generation assay for screening could be considered.

Abstract  Full-text [free] access

 

Self-reported HIV-positive status but subsequent HIV-negative test result using rapid diagnostic testing algorithms among seven sub-Saharan African military populations.

Harbertson J, Hale BR, Tran BR, Thomas AG, Grillo M, Jacobs MB, McAnany J, Shaffer RA. PLoS One. 2017 Jul 7;12(7):e0180796. doi: 10.1371/journal.pone.0180796. eCollection 2017.

HIV rapid diagnostic tests (RDTs) combined in an algorithm are the current standard for HIV diagnosis in many sub-Saharan African countries, and extensive laboratory testing has confirmed HIV RDTs have excellent sensitivity and specificity. However, false-positive RDT algorithm results have been reported due to a variety of factors, such as suboptimal quality assurance procedures and inaccurate interpretation of results. We conducted HIV serosurveys in seven sub-Saharan African military populations and recorded the frequency of personnel self-reporting HIV positivity, but subsequently testing HIV-negative during the serosurvey. The frequency of individuals who reported they were HIV-positive but subsequently tested HIV-negative using RDT algorithms ranged from 3.3 to 91.1%, suggesting significant rates of prior false-positive HIV RDT algorithm results, which should be confirmed using biological testing across time in future studies. Simple measures could substantially reduce false-positive results, such as greater adherence to quality assurance guidelines and prevalence-specific HIV testing algorithms as described in the World Health Organization's HIV testing guidelines. Other measures to improve RDT algorithm specificity include classifying individuals with weakly positive test lines as HIV indeterminate and retesting. While expansion of HIV testing in resource-limited countries is critical to identifying HIV-infected individuals for appropriate care and treatment, careful attention to potential causes of false HIV-positive results are needed to prevent the significant medical, psychological, and fiscal costs resulting from individuals receiving a false-positive HIV diagnosis.

Abstract  Full-text [free] access

 

Transitioning from antenatal surveillance surveys to routine HIV testing: a turning point in the mother-to-child transmission prevention programme for HIV surveillance in Brazil.

Pereira GFM, Sabidó M, Caruso A, Benzaken AS. BMC Infect Dis. 2017 Jul 5;17(1):469. doi: 10.1186/s12879-017-2540-4.

Background: In Brazil, due to the rapid increase in programmes for the prevention of mother-to-child transmission (PMTCT), routine programme data are widely available. The objective of this study was to assess the utility of programmatic data to replace HIV surveillance based on the antenatal care (ANC) surveillance survey (SS).

Methods: We analysed ANC SS data from 219 maternity service clinics. PMTCT variables were extracted from the ANC SS data collection form, which allowed us to capture and compare the ANC SS data and PMTCT HIV test results for each pregnant woman who completed the ANC SS. Both the PMTCT programme and the ANC SS tested for HIV using sequential ELISA and western blot for confirmation. We assessed the completeness (% missing) of the PMTC data included in the ANC SS.

Results: Of the 36 713 pregnant women who had ANC SS HIV tests performed, 30 588 also underwent PMTCT HIV testing. The HIV prevalence rate from routine PMTCT testing was 0.36%, compared to 0.38% from the ANC SS testing (relative difference -0.05%; absolute difference -0.02%). The relative difference in prevalence rates between pregnant women in northern Brazil and pregnant women central-west Brazil was -0.98 and 0.66, respectively. Of the 29 856 women who had HIV test results from both the PMTCT and ANC SS, the positive percent agreement of the PMTCT versus the surveillance test was 84.1% (95% confidence interval [CI]: 74.8-91.0), and the negative percent agreement was 99.9% (95% CI: 99.9-100.0). The PMTCT HIV testing uptake was 86.4%. The ANC SS HIV prevalence was 0.33% among PMTCT non-refusers and 0.59% among refusers, with a percent bias of -10.80% and a differential prevalence ratio of 0.56. Syphilis and HIV testing results were complete in 98% and 97.6% of PMTCT reports, respectively. The reported HIV status for the women at clinic entry was missing.

Conclusion: Although there were consistent HIV prevalence estimates from the PMTCT data and the ANC SS, the overall positive percent agreement of 84.1% falls below the World Health Organization benchmark of 94.7%. Therefore, Brazil must continue to reinforce data collection practices and ensure the quality of recently introduced rapid HIV testing before replacing the PMTCT data with surveillance techniques. However, some regions with better results could be prioritized to pilot the use of PMTCT data for surveillance.

Abstract  Full-text [free] access

 

Community burden of undiagnosed HIV infection among adolescents in Zimbabwe following primary healthcare-based provider-initiated HIV testing and counselling: A cross-sectional survey.

Simms V, Dauya E, Dakshina S, Bandason T, McHugh G, Munyati S, Chonzi P, Kranzer K, Ncube G, Masimirembwa C, Thelingwani R, Apollo T, Hayes R, Weiss HA, Ferrand RA. PLoS Med. 2017 Jul 25;14(7):e1002360. doi: 10.1371/journal.pmed.1002360. eCollection 2017 Jul.

Background: Children living with HIV who are not diagnosed in infancy often remain undiagnosed until they present with advanced disease. Provider-initiated testing and counselling (PITC) in health facilities is recommended for high-HIV-prevalence settings, but it is unclear whether this approach is sufficient to achieve universal coverage of HIV testing. We aimed to investigate the change in community burden of undiagnosed HIV infection among older children and adolescents following implementation of PITC in Harare, Zimbabwe.

Methods and Findings: Over the course of 2 years (January 2013-January 2015), 7 primary health clinics (PHCs) in southwestern Harare implemented optimised, opt-out PITC for all attendees aged 6-15 years. In February 2015-December 2015, we conducted a representative cross-sectional survey of 8-17-year-olds living in the 7 communities served by the study PHCs, who would have had 2 years of exposure to PITC. Knowledge of HIV status was ascertained through a caregiver questionnaire, and anonymised HIV testing was carried out using oral mucosal transudate (OMT) tests. After 1 participant taking antiretroviral therapy was observed to have a false negative OMT result, from July 2015 urine samples were obtained from all participants providing OMTs and tested for antiretroviral drugs to confirm HIV status. Children who tested positive through PITC were identified from among survey participants using gender, birthdate, and location. Of 7146 children in 4251 eligible households, 5486 (76.8%) children in 3397 households agreed to participate in the survey, and 141 were HIV positive. HIV prevalence was 2.6% (95% CI 2.2%-3.1%), and over a third of participants with HIV were undiagnosed (37.7%; 95% CI 29.8%-46.2%). Similarly, among the subsample of 2643 (48.2%) participants with a urine test result, 34.7% of those living with HIV were undiagnosed (95% CI 23.5%-47.9%). Based on extrapolation from the survey sample to the community, we estimated that PITC over 2 years identified between 18% and 42% of previously undiagnosed children in the community. The main limitation is that prevalence of undiagnosed HIV was defined using a combination of 3 measures (OMT, self-report, and urine test), none of which were perfect.

Conclusions: Facility-based approaches are inadequate in achieving universal coverage of HIV testing among older children and adolescents. Alternative, community-based approaches are required to meet the Joint United Nations Programme on HIV/AIDS (UNAIDS) target of diagnosing 90% of those living with HIV by 2020 in this age group.

Abstract  Full-text [free] access

  • share
0 comments.

Old fashioned AIDS is still with us – shocking in 2017

Editor’s notes: The term AIDS refers to advanced HIV disease with a CD4 count below 200 cells per microl. or with one of several typical opportunistic infections. It is more than twenty years since the revolutionary discovery of highly active combination antiretroviral therapy.  While deaths due to HIV have fallen steadily over the past two decades, it is shocking that so many people are still dying from AIDS.  In part this is due to the same issues of HIV testing discussed above.  The Centers for Disease Control and Prevention (CDC) published their most recent report on surveillance in the United States of America (USA).  The authors show very gradual progress in the right direction. But, still more than 20% of people are diagnosed with HIV infection in the USA when they already have AIDS.  In fact, in a further 20% of people, the stage of infection was not reported to CDC, so as a proportion of those with a known stage at diagnosis, as many as one quarter were diagnosed with AIDS. As might be expected, there are disparities between states with District of Columbia and California doing a little better.  There are big disparities by age (with over one third of people diagnosed at age greater than 45 years having AIDS) but surprisingly little difference by ethnicity.

Médecins sans Frontières (MSF) recently released a report highlighting the challenge of advanced disease, which was picked up in a commentary in the British Medical Journal by Cousins.  The report points out that in hospital settings in Democratic Republic of Congo, Guinea, Kenya, and Malawi, MSF are still seeing an alarmingly high mortality rate, with one third of deaths occurring within the first 48 hours of admission.  As many as three quarters of the patients had been on antiretroviral therapy (ART), suggesting that their advanced disease was not a consequence of late presentation, but rather of failure of the health system to deliver quality care.  The importance of detecting treatment failure early and changing to effective second (or third) line ART was emphasized.  Once patients do present to hospital with advanced HIV disease, it is a clinical emergency and urgent effective care may make a big difference.  WHO has recently issued guidance on managing advanced HIV disease, and the Journal of the International AIDS Society has recently released a useful supplement on Differentiated Care and HIV.

Back in the USA, Braunstein et al. used existing laboratory and other data to construct a retrospective analysis of what happened in the intervenable period during which different treatment approaches might have prevented more than 11 000 people from dying with HIV between 2007 and 2013.  The intervenable period was defined as the 12 months before the last three months of life.  The authors pointed out that in the last three months of life, people might be in care that was not typical of their engagement during the preceding year.  So the intervenable period is therefore more important to see where change could happen.  Like the MSF team, they found that a substantial proportion of people were not properly treated, as shown by the finding that 60% of people did not have a suppressed viral load in the period analysed.  This was despite 98% having some engagement with the health system as shown by laboratory records, 80% being defined as linked to care, and 76% being prescribed ART. The challenge seemed to be to provide high quality care with continuity of care and decisions made promptly according to the findings in the laboratory.

The package of interventions recommended by WHO in their guidance for people presenting with advanced HIV disease includes screening, treatment and/or prophylaxis for major opportunistic infections, rapid ART initiation and intensified adherence support interventions.  Additional support for this approach comes from the REALITY randomized trial conducted by Hakim and colleagues in Uganda, Zimbabwe, Malawi, and Kenya.  In this trial, people with advanced HIV infection, judged by their CD4 count, were randomized in a factorial design.  1805 participants were randomized to different ART regimens; to nutritional support or not; and to a package of prophylaxis.  This paper reports on the differences seen according to whether or not participants were randomized to receive the enhanced prophylaxis.  The package consisted of at least 12 weeks of co-trimoxazole (against pneumocystis, malaria, and various bacterial and protozoal infections), co-formulated with isoniazid and pyridoxine (against tuberculosis), along with fluconazole (against cryptococcus, candida and other fungi) also for 12 weeks and azithromycin (against a broader range of invasive bacteria including salmonella) for five days.  The enhanced prophylaxis led to a 27% reduction in mortality six months after entering the study, and there was still a clear difference after one year, by when 127 people had died in the standard of care group compared to 98 in the enhanced prophylaxis group.  Nonetheless, the death rate was still considerable.  It is also worth noting that many of the people in whom the CD4 count was extremely low did not complain of any symptoms.  So CD4 testing is still needed at the point of clinical care to determine who needs urgent differentiated care for advanced HIV infection.

The final paper in this section is a randomised trial from GHESKIO in Haiti (Koenig et al.).  The investigators randomized 701 people diagnosed with HIV, to start ART on the same day as their diagnosis, or to wait for three weeks, as is standard of care at the centre.  12 months later, viral suppression was somewhat better in people who started ART on the same day (61% vs. 52% at a cut-off of 1000 copies per ml.).  The authors point out that this was a single centre study, and results from GHESKIO might not be generalizable to other treatment sites in Haiti.  Although there were still substantial losses to follow up, there was clearly no evidence that the policy to start people on HIV treatment immediately was too hasty.

 

Missed opportunities: adapting the HIV care continuum to reduce HIV-related deaths

Braunstein SL, Robbins RS, Daskalakis DC. J Acquir Immune Defic Syndr. 2017 Jul 26. doi: 10.1097/QAI.0000000000001509. [Epub ahead of print]

Introduction: With advances in HIV care, persons with HIV/AIDS (PWHA) can lead healthy lives, but avoidable, HIV-related deaths continue to occur in New York City (NYC).

Methods: We selected PWHA from our surveillance registry who died between 2007-2013, resided in NYC, and survived ≥15 months post-diagnosis to generate an HIV Mortality Reduction Continuum of Care (HMRCC) describing pre-death care patterns among PWHA. We used HIV laboratory test reports to measure care outcomes during an "intervenable period" (IP) during which deaths may have been avoided. The continuum was stratified by underlying cause of death (COD) (HIV-related vs. other), and the HIV-related HMRCC was stratified by demographic characteristics.

Results: 11 187 analysis-eligible PWHA died during 2007-2013. 98% linked to care; 80% were retained in care during the IP; 66% were prescribed ART; 47% had VL≤1500 copies/mL; 40% achieved viral suppression (VS). Half (47%) of deaths were HIV-related. Retention was higher among HIV-related COD (83% vs. 78%), but VS was lower (34% vs. 46%). The HIV-related HMRCC revealed disparities in VS. Despite comparable retention rates, Whites had the highest VS (42%, vs. 32% Blacks and 33% Latinos/Hispanics). Additionally, retention and VS increased with increasing age. People with a history of injection drug use had relatively high rates of retention (88%) and VS (37%).

Discussion: The HMRCC is a novel framework for evaluating pre-death care patterns among PWHA and identifying opportunities to reduce preventable deaths. In NYC, reducing mortality will require increasing VS among those already in care, particularly for Blacks and Latinos/Hispanics.

Abstract access

 

Enhanced prophylaxis plus antiretroviral therapy for advanced HIV infection in Africa

Hakim J, Musiime V, Szubert AJ, Mallewa J, Siika A, Agutu C, Walker S, Pett SL, Bwakura-Dangarembizi M, Lugemwa A, Kaunda S, Karoney M, Musoro G, Kabahenda S, Nathoo K, Maitland K, Griffiths A, Thomason MJ, Kityo C, Mugyenyi P, Prendergast AJ, Walker AS, Gibb DM; REALITY Trial Team. N Engl J Med. 2017 Jul 20;377(3):233-245. doi: 10.1056/NEJMoa1615822.

Background: In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%.

Methods: In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (co-formulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim-sulfamethoxazole alone). The primary end point was 24-week mortality.

Results: A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan-Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups.

Conclusion: Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects.

Abstract  Full-text [free] access

 

Same-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trial

Koenig SP, Dorvil N, Dévieux JG, Hedt-Gauthier BL, Riviere C, Faustin M, Lavoile K, Perodin C, Apollon A, Duverger L, McNairy ML, Hennessey KA, Souroutzidis A, Cremieux PY, Severe P, Pape JW. PLoS Med. 2017 Jul 25;14(7):e1002357. doi: 10.1371/journal.pmed.1002357. eCollection 2017 Jul.

Background: Attrition during the period from HIV testing to antiretroviral therapy (ART) initiation is high worldwide. We assessed whether same-day HIV testing and ART initiation improves retention and virologic suppression.

Methods and Findings: We conducted an unblinded, randomized trial of standard ART initiation versus same-day HIV testing and ART initiation among eligible adults ≥18 years old with World Health Organization Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. The study was conducted among outpatients at the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic infections (GHESKIO) Clinic in Port-au-Prince, Haiti. Participants were randomly assigned (1:1) to standard ART initiation or same-day HIV testing and ART initiation. The standard group initiated ART 3 weeks after HIV testing, and the same-day group initiated ART on the day of testing. The primary study endpoint was retention in care 12 months after HIV testing with HIV-1 RNA <50 copies/ml. We assessed the impact of treatment arm with a modified intention-to-treat analysis, using multivariable logistic regression controlling for potential confounders. Between August 2013 and October 2015, 762 participants were enrolled; 59 participants transferred to other clinics during the study period, and were excluded as per protocol, leaving 356 in the standard and 347 in the same-day ART groups. In the standard ART group, 156 (44%) participants were retained in care with 12-month HIV-1 RNA <50 copies, and 184 (52%) had <1000 copies/ml; 20 participants (6%) died. In the same-day ART group, 184 (53%) participants were retained with HIV-1 RNA <50 copies/ml, and 212 (61%) had <1000 copies/ml; 10 (3%) participants died. The unadjusted risk ratio (RR) of being retained at 12 months with HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard ART group, and the unadjusted RR for being retained with HIV-1 RNA <1000 copies was 1.18 (95% CI: 1.04, 1.31; p = 0.012). The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain.

Conclusions: Same-day HIV testing and ART initiation is feasible and beneficial in this setting, as it improves retention in care with virologic suppression among patients with early clinical HIV disease.

Abstract  Full-text [free] access

  • share
0 comments.

Understanding different levels and different models of integration

Editor’s notes: Integration between HIV services and programmes and other services and programmes sounds like common sense.  As people with HIV live longer they are more likely to develop other chronic conditions.  Some of these conditions may also be exacerbated by some anti-retroviral medicines, although modern treatment regimens have much less effect on lipid and insulin metabolism.  Low grade chronic inflammation may continue even in people whose HIV is suppressed and people whose CD4 count sunk to a low level before starting seem to be at greater risk of subsequent cardiovascular disease.  Then there are diseases that are more common among people living with HIV, such as tuberculosis and invasive cervical cancer.  And HIV programmes around the world have established some of the best clinical services for chronic care, with regular appointments, decentralized follow-up, algorithmic approaches to clinical changes and so on.  So it seems sensible to look for the synergies and build on them.

However, research on integration makes it clear that there are many different interpretations of what integration should or could mean.  In different epidemiological settings, the priorities will inevitably be very different.  Two useful systematic reviews this month by the same team, review this territory for cardiovascular diseases, diabetes and cervical cancer. 

Haldane et al. distinguish between the levels of integration.  Micro level integration involves direct patient care and adjusting diagnosis, treatment and support appropriately.  Meso level integration refers to changes made at the clinic or delivery system level, while macro level integration is about programme management, supply chains and systems organisation.  Despite a large literature (over 7600 papers) on the overlaps between HIV and cardiovascular diseases and diabetes, the authors found only 14 studies that allowed aspects of the integration to be assessed, and only one of these evaluated outcomes.  The others were descriptive studies which highlighted many innovative models, almost all at the meso-level.

Similarly for invasive cervical cancer, which is at least four times as common among women living with HIV as seronegative women, Sigfrid et al. found many papers but only 21 that met their inclusion criteria.  Their models of integration could all be said to be at the meso-level, with one stop shops; co-located services or more complex integrated pathways described.  Again, there were no good evaluations of the outcomes of these systematic changes to the way that services are delivered.  In most countries, all women with cervical cancer should at least be offered an HIV test and appropriate linkage to care expedited for those found to be seropositive.  Women living with HIV need regular screening for early cervical cancer and (as discussed last month) screening for human papillomavirus, the underlying cause of cervical cancer.  However, many ART clinics are now busy and crowded so that even if staff are trained, they do not have time or space or privacy to do cervical examinations.  HPV vaccination campaigns need to be carried out in schools before girls become sexually active.  This could be a good time to engage with sexuality education. However, many campaigns have tended to avoid the challenges of discussing sex with girls who are not yet sexually active, preferring to focus on the vaccine as a cancer prevention tool.  So, the lesson from both these papers is that we need to define more rigorously what we want to achieve with integration and then ensure that we evaluate whether or not our interventions achieve it.

Tuberculosis and HIV have been dancing together since the first descriptions of HIV in the 1980s.  The large majority of tuberculosis patients in many countries are now screened for HIV, with appropriate referral and increasing numbers of people living with HIV are screened regularly for the four classic symptoms of tuberculosis (weight loss, cough, night sweats and fever) and referred onwards for diagnosis.  Yet we still find that collaboration between programmes is not always easy. The number of people living with HIV who are also on tuberculosis treatment reported by the HIV programme may not be the same as the number of people on tuberculosis treatment who are also living with HIV reported by the tuberculosis programme.  Osei et al. report from the Volta Region of Ghana that more than 90% of tuberculosis patients had an HIV test recorded in the tuberculosis register, with an HIV prevalence of 18%.  As has been reported frequently elsewhere, the authors found that HIV was commoner in those with smear negative tuberculosis, and the outcome of treatment was less good.  Their recommendation for strengthening the collaboration between tuberculosis and HIV makes sense, although it has been WHO policy for many years.

The WHO guidance on collaborative TB/HIV activities has always included isoniazid preventive therapy.  However, this remains poorly implemented for reasons that are never very clear.  Despite no good evidence, many tuberculosis programme staff and clinicians worry about the risk of generating isoniazid resistant tuberculosis.  Many HIV programme staff feel that isoniazid remains in the realm of the tuberculosis programme, so that although they are happy to promote cotrimoxazole, they are much slower to prescribe isoniazid.  Many also feel that ART alone should be sufficient to prevent tuberculosis, despite randomized trials in high prevalence settings that demonstrate the additional benefits of isoniazid.  Shayo et al. make a strong economic argument for promoting isoniazid in their study in Tanzania.  They base their model on the rates of tuberculosis and mortality seen during the expansion of pilot programmes for isoniazid in Dar es Salaam.  Both tuberculosis and mortality were significantly lower in the clinics which were part of the pilot programme.  In fact, mortality was approximately tenfold lower, which seems unlikely to be simply due to isoniazid.  Some studies such as TEMPRANO have shown a mortality benefit from isoniazid, while many trials have failed to do so.  Given the non-randomized nature of the comparison, the authors do point out that their conclusions must be tentative.  Nonetheless, it is a convincing demonstration that isoniazid preventive therapy can be incorporated into a busy HIV care clinic and there is abundant evidence that this is the right thing to do.

One more tuberculosis study this month was carried out in Germany.  Karo et al. reviewed the immunology of the 139 people who developed tuberculosis among more than 10 000 people living with HIV in the German ClinSurv cohort.  The authors excluded people who already had tuberculosis at the time that HIV was diagnosed, and found that new diagnoses of tuberculosis were most common in the first couple of years after starting ART.  The authors also show that immune restoration was slower in people who developed tuberculosis.  There was still some deficit up to seven years after ART was started.  Again, their conclusion is that we should be using isoniazid to prevent tuberculosis in people living with HIV, especially people who have spent much of their lives in areas of the world, such as sub-Saharan Africa where tuberculosis is much more prevalent than in Europe.  It is often said that Mycobacterium tuberculosis is a very slow growing organism.  We must work harder to ensure that our response to it is not very slow too.  Tuberculosis remains the biggest killer of people with HIV in most of the world, yet for years we have known that a simple, cheap, non-toxic treatment can prevent it. 

 

Integrating cardiovascular diseases, hypertension, and diabetes with HIV services: a systematic review.

Haldane V, Legido-Quigley H, Chuah FLH, Sigfrid L, Murphy G, Ong SE, Cervero-Liceras F, Watt N, Balabanova D, Hogarth S, Maimaris W, Buse K, McKee M, Piot P, Perel P. AIDS Care. 2017 Jul 5:1-13. doi:10.1080/09540121.2017.1344350. [Epub ahead of print]

Non-communicable diseases (NCDs), including cardiovascular diseases (CVD), hypertension and diabetes together with HIV infection are among the major public health concerns worldwide. Health services for HIV and NCDs require health systems that provide for people's chronic care needs, which present an opportunity to coordinate efforts and create synergies between programs to benefit people living with HIV and/or AIDS and NCDs. This review included studies that reported service integration for HIV and/or AIDS with coronary heart diseases, chronic CVD, cerebrovascular diseases (stroke), hypertension or diabetes. We searched multiple databases from inception until October 2015. Articles were screened independently by two reviewers and assessed for risk of bias. 11 057 records were identified with 7 616 after duplicate removal. After screening titles and abstracts, 14 papers addressing 17 distinct interventions met the inclusion criteria. We categorized integration models by diseases (HIV with diabetes, HIV with hypertension and diabetes, HIV with CVD and finally HIV with hypertension and CVD and diabetes). Models also looked at integration from micro (patient focused integration) to macro (system level integrations). Most reported integration of hypertension and diabetes with HIV and AIDS services and described multidisciplinary collaboration, shared protocols, and incorporating screening activities into community campaigns. Integration took place exclusively at the meso-level, with no micro- or macro-level integrations described. Most were descriptive studies, with one cohort study reporting evaluative outcomes. Several innovative initiatives were identified and studies showed that CVD and HIV service integration is feasible. Integration should build on existing protocols and use the community as a locus for advocacy and health services, while promoting multidisciplinary teams, including greater involvement of pharmacists. There is a need for robust and well-designed studies at all levels - particularly macro-level studies, research looking at long-term outcomes of integration, and research in a more diverse range of countries.

Abstract access 

 

Integrating cervical cancer with HIV healthcare services: A systematic review.

Sigfrid L, Murphy G, Haldane V, Chuah FLH, Ong SE, Cervero-Liceras F, Watt N, Alvaro A, Otero-Garcia L, Balabanova D, Hogarth S, Maimaris W, Buse K, Mckee M, Piot P, Perel P, Legido-Quigley H. PLoS One. 2017 Jul 21;12(7):e0181156. doi: 10.1371/journal.pone.0181156. eCollection 2017.

Background: Cervical cancer is a major public health problem. Even though readily preventable, it is the fourth leading cause of death in women globally. Women living with HIV are at increased risk of invasive cervical cancer, highlighting the need for access to screening and treatment for this population. Integration of services has been proposed as an effective way of improving access to cervical cancer screening especially in areas of high HIV prevalence as well as lower resourced settings. This paper presents the results of a systematic review of programs integrating cervical cancer and HIV services globally, including feasibility, acceptability, clinical outcomes and facilitators for service delivery.

Methods: This is part of a larger systematic review on integration of services for HIV and non-communicable diseases. To be considered for inclusion studies had to report on programs to integrate cervical cancer and HIV services at the level of service delivery. We searched multiple databases including Global Health, Medline and Embase from inception until December 2015. Articles were screened independently by two reviewers for inclusion and data were extracted and assessed for risk of bias.

Main results: 11 057 records were identified initially. 7616 articles were screened by title and abstract for inclusion. A total of 21 papers reporting interventions integrating cervical cancer care and HIV services met the criteria for inclusion. All but one study described integration of cervical cancer screening services into existing HIV services. Most programs also offered treatment of minor lesions, a 'screen-and-treat' approach, with some also offering treatment of larger lesions within the same visit. Three distinct models of integration were identified. One model described integration within the same clinic through training of existing staff. Another model described integration through co-location of services, with the third model describing programs of integration through complex coordination across the care pathway. The studies suggested that integration of cervical cancer services with HIV services using all models was feasible and acceptable to patients. However, several barriers were reported, including high loss to follow up for further treatment, limited human-resources, and logistical and chain management support. Using visual screening methods can facilitate screening and treatment of minor to larger lesions in a single 'screen-and-treat' visit. Complex integration in a single-visit was shown to reduce loss to follow up. The use of existing health infrastructure and funding together with comprehensive staff training and supervision, community engagement and digital technology were some of the many other facilitators for integration reported across models.

Conclusions: This review shows that integration of cervical cancer screening and treatment with HIV services using different models of service delivery is feasible as well as acceptable to women living with HIV. However, the descriptive nature of most papers and lack of data on the effect on long-term outcomes for HIV or cervical cancer limits the inference on the effectiveness of the integrated programs. There is a need for strengthening of health systems across the care continuum and for high quality studies evaluating the effect of integration on HIV as well as on cervical cancer outcomes.

Abstract  Full-text [free] access 

 

The burden of HIV on tuberculosis patients in the Volta region of Ghana from 2012 to 2015: implication for tuberculosis control.

Osei E, Der J, Owusu R, Kofie P, Axame WK. BMC Infect Dis. 2017 Jul 19;17(1):504. doi: 10.1186/s12879-017-2598-z.

Background: The impact of HIV on TB, and the implications for TB control, has been acknowledged as a public health challenge. It is imperative therefore to assess the burden of HIV on TB patients as an indicator for monitoring the control efforts of the two diseases in this part of the world. This study aimed at determining the burden of HIV infection in TB patients.

Methods: We conducted a retrospective review of TB registers in five districts of the Volta Region of Ghana. Prevalence of TB/HIV co-infection was determined. Bivariate and multivariate logistic regression were used to identify the predictors of HIV infection among TB patients and statistical significance was set at p-value <0.05.

Results: Of the 1772 TB patients, 1633 (92.2%) were tested for HIV. The overall prevalence of TB/HIV co-infection was (18.2%; 95% CI: 16.4-20.1). The prevalence was significantly higher among females (24.1%; 95%CI: 20.8-27.7), compared to males (15.1%; 95% CI: 13.1-17.4) (p < 0.001) and among children <15 years of age (27.0%; 95% CI: 18.2-38.1), compared to the elderly ≥70 years (3.5%; 95% CI: 1.6-7.4) (p < 0.001). Treatment success rate was higher among patients with only TB (90%; 95% CI: 88.1-91.5) than among TB/HIV co-infected patients (77.0%; 95% CI: 71.7-81.7) (p < 0.001). Independent predictors of HIV infection were found to be: being female (AOR: 1.79; 95% CI: 1.38-2.13; p < 0.001); smear negative pulmonary TB (AOR: 1.84; 95% CI: 1.37-2.47; p < 0.001); and patients registered in Hohoe, Kadjebi, and Kpando districts with adjusted odds ratios of 1.69 (95% CI: 1.13-2.54; p = 0.011), 2.29 (95% CI: 1.46-3.57; p < 0.001), and 2.15 (95% CI: 1.44-3.21; p < 0.001) respectively. Patients ≥70 years of age and those registered in Keta Municipal were less likely to be HIV positive with odds ratios of 0.09 (95% CI: 0.04-0.26; p < 0.001) and 0.62 (95% CI: 0.38-0.99; p = 0.047) respectively.

Conclusion: TB/HIV co-infection rate in five study districts of the Volta region is quite high, occurs more frequently in female patients than males; among smear negative pulmonary TB patients, and children <15 years of age. Findings also demonstrate that HIV co-infection affects TB treatment outcomes adversely. Strengthening the TB/HIV collaborative efforts is required in order to reduce the burden of co-infection in patients.

Abstract  Full-text [free] access                                                         

 

Cost-effectiveness of isoniazid preventive therapy among HIV-infected patients clinically screened for latent tuberculosis infection in Dar es Salaam, Tanzania: a prospective cohort study.

Shayo GA, Chitama D, Moshiro C, Aboud S, Bakari M, Mugusi F. BMC Public Health. 2017 Jul 19;18(1):35. doi: 10.1186/s12889-017-4597-9.

Background: One of the reasons why Isoniazid preventive therapy (IPT) for Tuberculosis (TB) is not widely used in low income countries is concerns on cost of excluding active TB. We analyzed the cost-effectiveness of IPT provision in Tanzania having ruled out active TB by a symptom-based screening tool.

Methods: Data on IPT cost-effectiveness was prospectively collected from an observational cohort study of 1283 HIV-infected patients on IPT and 1281 controls; followed up for 24 months. The time horizon for the analysis was 2 years. Number of TB cases prevented and deaths averted were used for effectiveness. A micro costing approach was used from a provider perspective. Cost was estimated on the basis of clinical records, market price or interviews with medical staff. We annualized the cost at a discount of 3%. A univariate sensitivity analysis was done. Results are presented in US$ at an average annual exchange rate for the year 2012 which was Tanzania shillings 1562.4 for 1 US $.

Results: The number of TB cases prevented was 420/100 000 persons receiving IPT. The number of deaths averted was 979/100 000 persons receiving IPT. Incremental cost due to IPT provision was US$ 170 490. The incremental cost-effective ratio was US $ 405.93 per TB case prevented and US $ 174.15 per death averted. These costs were less than 3 times the 768 US $ Gross Domestic Product (GDP) per capita for Tanzania in the year 2014, making IPT provision after ruling out active TB by the symptom-based screening tool cost-effective. The results were robust to changes in laboratory and radiological tests but not to changes in recurrent, personnel, medication and utility costs.

Conclusion: IPT should be given to HIV-infected patients who screen negative to symptom-based TB screening questionnaire. Its cost-effectiveness supports government policy to integrate IPT to HIV/AIDS care and treatment in the country, given the availability of budget and the capacity of health facilities.

Abstract  Full-text [free] access 

 

Immunological recovery in tuberculosis/HIV co-infected patients on antiretroviral therapy: implication for tuberculosis preventive therapy.

Karo B, Krause G, Castell S, Kollan C, Hamouda O, Haas W; ClinSurv HIV Study Group. BMC Infect Dis. 2017 Jul 25;17(1):517. doi: 10.1186/s12879-017-2627-y.

Background: Understanding the immune response to combination antiretroviral therapy (cART) is essential for a clear approach to tuberculosis (TB) preventive therapy. We investigated the immunological recovery in cART-treated HIV-infected patients developing TB compared to those who remained free of TB.

Methods: We extracted data of HIV-infected patients from a multicenter cohort for the HIV clinical surveillance in Germany. No patients included in our study had TB at the beginning of the observation. Using a longitudinal mixed model, we assessed the differences in the mean change of biomarkers (CD4+ cell count, CD8+ cell count, CD4:CD8 ratio and viral load) since cART initiation in patients who remained free of TB vs. those developing TB. To detect the best-fit trajectories of the immunological biomarkers, we applied a multivariable fractional polynomials model.

Results: We analyzed a total of 10 671 HIV-infected patients including 139 patients who developed TB during follow-up. The highest TB incidences were observed during the first two years since cART initiation (0.32 and 0.50 per 100 person-years). In an adjusted multivariable mixed model, we found that the average change in CD4+ cell count recovery was significantly greater by 33 cells/μl in patients who remained free of TB compared with those developing TB. After the initial three months of cART, 65.6% of patients who remaining free of TB achieved CD4+ count of ≥400 cells/μl, while only 11.3% of patients developing TB reached this immunological status after the three months of cART. We found no differences in the average change of CD8+ cell count, CD4:CD8 ratio or viral load between the two-patient groups.

Conclusion: All HIV-infected patients responded to cART. However, patients developing TB showed reduced recovery in CD4+ cell count and this might partly explain the incident TB in HIV-infected patients receiving cART. These findings reinforce the importance of adjunctive TB preventive therapy for patients with reduced recovery in CD4+ cell count.

Abstract  Full-text [free] access 

  • share
0 comments.

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.

Abstract access 

  • share
0 comments.

We still lack good data on many specific populations that are most severely affected by HIV

Editor’s notes: Transgender women are often under-represented in HIV research.  Yet they face many challenges in day to day life with discrimination at many levels.  Employment opportunities are few and many transgender women make a living through sex work.  It is well recognized that they are at specific and increased risks of HIV. Yet many intervention trials group them with gay men and other men who have sex with men, often meaning that the results cannot be disaggregated into more meaningful categories.  The number of transgender women in particular studies is also often too small to make strong conclusions from the data they provide to the study.  So it is encouraging to see Grinsztejn and colleagues establishing a major study specifically in the community of transgender women in Rio de Janeiro, Brazil.  The authors recruited 345 transgender women through a respondent driven sampling process.  This non-random approach is necessitated by the nature of the population, as it would not be possible to make a complete sampling frame from census or other documentation.  However, statistical approaches to make best estimates of population measures are available and the authors found that almost one third of the women were living with HIV and that 29% had not previously been tested for HIV.  The high frequency of other sexually transmitted infections highlights the need for better engagement and services not just for HIV but for their wider sexual and reproductive health and rights needs.

Another population that is under-researched is people with disabilities.  “There is a tribe of Ugandans . . . whose issues and needs have not been given their due and appropriate attention in the fight. By all indications, persons with disabilities have been forgotten, consciously and unconsciously. They represent the forgotten tribe” (Mwesigwa Martin Babu, 2005). Abimanyi-Ochom and colleagues used data collected during the 2011 Ugandan demographic and health survey, which included questions about disabilities for the first time.  While HIV knowledge is similar in those with and without disabilities, people living with disabilities reported indicators of increased risk of acquiring HIV.  Findings included slightly earlier sexual debut and a higher frequency of reported sexually transmitted infections.  Other studies have demonstrated that people living with disabilities may have lower self-esteem and self-efficacy and that abuse, including sexual abuse is more common among this group than among their peers.

The findings are reinforced by a study from Cameroon.  De Beaudrap and colleagues used the same questionnaire that had been used in the Uganda DHS (the Washington short set of questions on disability) to identify people living with disability in a random sample of the population in Yaounde.  The prevalence of HIV was almost twice as high among those with disability than among controls matched by age, sex and residential area.  In line with the discussion in the Ugandan paper, the authors in Cameroon found that women with disability were more likely to receive money for sex and to be victims of sexual violence.  Both of these characteristics were, not surprisingly, associated with still higher rates of HIV infection.  Both papers call for more and better data and we also need to develop and test interventions to reduce the burden of HIV among those living with disabilities.

Unveiling of HIV dynamics among transgender women: a respondent-driven sampling study in Rio de Janeiro, Brazil.

Grinsztejn B, Jalil EM, Monteiro L, Velasque L, Moreira RI, Garcia AC, Castro CV, Krüger A, Luz PM, Liu AY, McFarland W, Buchbinder S, Veloso VG, Wilson EC; Transcender Study Team. Lancet HIV. 2017 Apr;4(4):e169-e176. doi: 10.1016/S2352-3018(17)30015-2. Epub 2017 Feb 8.

Background: The burden of HIV in transgender women (transwomen) in Brazil remains unknown. We aimed to estimate HIV prevalence among transwomen in Rio de Janeiro and to identify predictors of newly diagnosed HIV infections.

Methods: We recruited transwomen from Rio de Janeiro, Brazil, by respondent-driven sampling. Eligibility criteria were self-identification as transwomen, being 18 years of age or older, living in Rio de Janeiro or its metropolitan area, and having a valid peer recruitment coupon. We recruited 12 seed participants from social movements and formative focus groups who then used peer recruitment coupons to refer subsequent peers to the study. We categorised participants as HIV negative, known HIV infected, or newly diagnosed as HIV infected. We assessed predictors of newly diagnosed HIV infections by comparing newly diagnosed with HIV-negative participants. We derived population estimates with the Respondent-Driven Sampling II estimator.

Findings: Between Aug 1, 2015, and Jan 29, 2016, we enrolled 345 eligible transwomen. 29·1% (95% CI 23·2-35·4) of participants had no previous HIV testing (adjusted from 60 participants), 31·2% (18·8-43·6) had HIV infections (adjusted from 141 participants), and 7·0% (0·0-15·9) were newly diagnosed as HIV infected (adjusted from 40 participants). We diagnosed syphilis in 28·9% (18·0-39·8) of participants, rectal chlamydia in 14·6% (5·4-23·8), and gonorrhoea in 13·5% (3·2-23·8). Newly diagnosed HIV infections were associated with black race (odds ratio 22·8 [95% CI 2·9-178·9]; p=0·003), travesti (34·1 [5·8-200·2]; p=0·0001) or transsexual woman (41·3 [6·3-271·2]; p=0·0001) gender identity, history of sex work (30·7 [3·5-267·3]; p=0·002), and history of sniffing cocaine (4·4 [1·4-14·1]; p=0·01).

Interpretation: Our results suggest that transwomen bear the largest burden of HIV among any population at risk in Brazil. The high proportion of HIV diagnosis among young participants points to the need for tailored long-term health-care and prevention services to curb the HIV epidemic and improve the quality of life of transwomen in Brazil.

Abstract access 

HIV/AIDS knowledge, attitudes and behaviour of persons with and without disabilities from the Uganda demographic and health survey 2011: differential access to HIV/AIDS information and services.

Abimanyi-Ochom J, Mannan H, Groce NE, McVeigh J  PLoS One. 2017 Apr 13;12(4):e0174877. doi: 10.1371/journal.pone.0174877. eCollection 2017.

Uganda is among the first to use the Washington Group Short Set of Questions on Disability to identify persons with disabilities in its Demographic and Health Survey. In this paper, we review the HIV knowledge, attitudes and behaviour component of the 2011 Ugandan demographic and health survey, analysing a series of questions comparing those with and without disabilities in relation to HIV/AIDS knowledge, attitudes and practices. We found comparable levels of knowledge on HIV/AIDS for those with and those without disabilities in relation to HIV transmission during delivery (93.89%, 93.26%) and through breastfeeding (89.91%, 90.63%), which may reflect increased attention to reaching the community of persons with disabilities. However, several gaps in the knowledge base of persons with disabilities stood out, including misconceptions of risk of HIV infection through mosquito bites and caring for a relative with HIV in own household (34.39%, 29.86%; p<0.001; 91.53%, 89.00%; p = 0.001, respectively). The issue is not just access to appropriate information but also equitable access to HIV/AIDS services and support. Here we found that persons with multiple disabilities were less likely than individuals without disabilities to return to receive results from their most recent HIV test (0.60[0.41-0.87], p<0.05). HIV testing means little if people do not return for follow-up to know their HIV status and, if necessary, to be connected to available services and supports. Additional findings of note were that persons with disabilities reported having a first sexual encounter at a slightly younger age than peers without disabilities; and persons with disabilities also reported having a sexually transmitted disease (STD) within the last 12 months at significantly higher rates than peers without disabilities (1.38[1.18-1.63], p<0.01), despite reporting comparable knowledge of the need for safer sex practices. This analysis is among the first to use HIV/AIDS-related questions from Demographic Health Surveys to provide information about persons with disabilities in Uganda in comparison to those without disabilities. These findings present a more complex and nuanced understanding of persons with disabilities and HIV/AIDS. If persons with disabilities are becoming sexually active earlier, are more likely to have an STD within the preceding 12 month period and are less likely to receive HIV test results, it is important to understand why. Recommendations are also made for the inclusion of disability measures in Uganda's AIDS Indicator Survey to provide cyclical and systematic data on disability and HIV/AIDS, including HIV prevalence amongst persons with disabilities.

Abstract Full-text [free] access 

Prevalence of HIV infection among people with disabilities: a population-based observational study in Yaoundé, Cameroon (HandiVIH).

De Beaudrap P, Beninguisse G, Pasquier E, Tchoumkeu A, Touko A, Essomba F, Brus A, Aderemi TJ, Hanass-Hancock J, Eide AH, Mac-Seing M, Mont D. Lancet HIV. 2017 Apr;4(4):e161-e168. doi: 10.1016/S2352-3018(16)30209-0. Epub 2017 Jan 24.

Background: In resource-limited settings, people with disabilities have been left behind in the response to HIV. In the HandiVIH study, we estimate and compare HIV prevalence and associated risk factors between people with and without disabilities.

Methods: In this cross-sectional, population-based, observational study, we used two-phase random sampling to recruit adults with disabilities and a control group matched for age, sex, and residential location from households of the general population. We used the Washington Group Short Set of Questions on Disability to identify people with disabilities. We administered an HIV test and a life-course history interview to participants. The primary outcome was the prevalence of HIV among participants with and without disabilities.

Findings: Between Oct 2, 2014, and Nov 30, 2015, we recruited 807 people with disabilities and 807 participants without disabilities from Yaoundé, Cameroon. 28 of 716 people in the control population had a positive HIV test result (crude prevalence 3·9%, 95% CI 2·9-5·3) compared with 50 of 739 people with disabilities (6·8%, 5·0-8·6; conditional odds ratio [OR] 1·7; p=0·04). Women with disabilities were more often involved in paid sexual relationships than were women without disabilities (2·5% vs 0·5%, p=0·05). People with disabilities were also at increased risk of sexual violence than were women without disabilities (11·0% vs 7·5%, OR 1·5; p=0·01). Sexual violence and sex work were strongly associated with increased risk of HIV infection among participants with disabilities but not among controls (OR 3·0, 95% CI 1·6-5·6 for sexual violence and 12·3, 4·4-34·6 for sex work). Analyses were done in men and women.

Interpretation: The higher prevalence of HIV infection in people with disabilities than people without disabilities reflects a higher exposure to HIV infection as well as the presence of disability-associated HIV infection. The susceptibility of people with disabilities to HIV infection seems to be shaped by social and environmental factors. Research is needed to inform firm recommendations on how to protect this vulnerable population.

Abstract access 

Africa, Latin America
Brazil, Cameroon, Uganda
  • share
0 comments.

Short and sweet? Do study participants prefer shorter or longer consent forms? Do they understand the contents?

Editor’s notes: As described above in the HOLA en Grupos study, engagement and partnership is vital if HIV research is to produce useful and relevant results.  The ethics of research involving human subjects continues to evolve but the key principles laid out by Beauchamp and Childress in 1989 remain central.  The principles of autonomy, non-maleficence, beneficence, and justice, have been extremely influential in the field of medical ethics, and are fundamental for understanding the current approach to ethical assessment in health care.

Autonomy implies that research participants should be able to consent willingly to join a research study and a key part of that informed consent process is usually a written “consent form” that is signed by the participant.  However, a major challenge is often to ensure that on the one hand all relevant information about possible benefits and harms is included in the information and on the other hand that the consent process is manageable and appropriate for the participant.

In the largest study of its kind to date, Grady and colleagues embedded a randomized trial within the larger randomized START trial (comparing immediate with deferred start of antiretroviral medicines in people with early HIV infection).  Around 4000 participants in START were allocated according to their 154 research sites, which were randomly assigned to the original, lengthy and somewhat complicated consent form, or to a simplified, shorter consent form with much more attention paid to ease of comprehension and readability.  The shorter form was still around 1800 words long (compared to the almost 6000 of the original) and was only a little easier to read, because the sponsors of the study needed to be certain that all the information demanded by current guidelines was included.

Surprisingly, there was no overall difference in either the primary outcome (an understanding that participants’ treatment would be randomly allocated) or in overall comprehension of aspects of the study.  In other words, the authors did NOT find the advantages that they were expecting from the modified consent form.

However, various clear trends emerge from the data that are relevant to future research too.  Those with less education were clearly less able to understand the randomization approach.  73% of the 1240 participants who had not attended high school compared to more than 90% of the 935 who had completed a university degree or postgraduate education answered the primary question on randomization correctly. The START study team were diligent in explaining the study to potential participants before presenting the informed consent form, with around a half of participants reporting more than an hour of explanation prior to being asked for consent, and more than 80% of sites reporting that participants understood the study “very well” prior to the consent process.  There was also a clear trend for participants from sites that had been involved in previous HIV research to understand the process better (rising from 69% in those with no previous HIV studies to 85% in those with more than 10).

Increasingly HIV prevention researchers are aiming to work with populations that have high ongoing incidence of HIV.  In a world where treatment is increasingly widespread and overall numbers of infections have fallen somewhat, this means that researchers will tend to be working with more and more disadvantaged populations where many participants may be less well educated and less familiar with research.  This important study makes it clear that the ethical principle of autonomy requires an ongoing process that goes far beyond the choice of words in a consent form.  Research must build trust between researchers and participants.  The research team should explain carefully and in appropriate ways what is involved in the study and what options participants have. Study teams should build a governance process into the research so that participants can have confidence that any risks of the research, both for them as individuals, but also often for the community or group to which they belong, are monitored and mitigated.  In this way potentially vulnerable individuals may still be recruited into important research projects and contribute to the ways in which science can end the epidemic.

A randomized trial comparing concise and standard consent forms in the START trial.

Grady C, Touloumi G, Walker AS, Smolskis M, Sharma S, Babiker AG, Pantazis N, Tavel J, Florence E, Sanchez A, Hudson F, Papadopoulos A, Emanuel E, Clewett M, Munroe D, Denning E; INSIGHT START Informed Consent substudy Group PLoS One. 2017 Apr 26;12(4):e0172607. doi: 10.1371/journal.pone.0172607. eCollection 2017.

Background: Improving the effectiveness and efficiency of research informed consent is a high priority. Some express concern about longer, more complex, written consent forms creating barriers to participant understanding. A recent meta-analysis concluded that randomized comparisons were needed.

Methods: We conducted a cluster-randomized non-inferiority comparison of a standard versus concise consent form within a multinational trial studying the timing of starting antiretroviral therapy in HIV+ adults (START). Interested sites were randomized to standard or concise consent forms for all individuals signing START consent. Participants completed a survey measuring comprehension of study information and satisfaction with the consent process. Site personnel reported usual site consent practices. The primary outcome was comprehension of the purpose of randomization (pre-specified 7.5% non-inferiority margin).

Results: 77 sites (2429 participants) were randomly allocated to use standard consent and 77 sites (2000 participants) concise consent, for an evaluable cohort of 4229. Site and participant characteristics were similar for the two groups. The concise consent was non-inferior to the standard consent on comprehension of randomization (80.2% versus 82%, site adjusted difference: 0.75% (95% CI -3.8%, +5.2%)); and the two groups did not differ significantly on total comprehension score, satisfaction, or voluntariness (p>0.1). Certain independent factors, such as education, influenced comprehension and satisfaction but not differences between consent groups.

Conclusions: An easier to read, more concise consent form neither hindered nor improved comprehension of study information nor satisfaction with the consent process among a large number of participants. This supports continued efforts to make consent forms more efficient.

Trial registration: Informed consent substudy was registered as part of START study in clinicaltrials.gov #NCT00867048, and EudraCT # 2008-006439-12.

Abstract Full-text [free] access 

  • share
0 comments.

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.

Abstract access 

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.

Abstract access 

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.

Abstract access 

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.

Abstract access 

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.

Abstract access 

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.

Abstract access 

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.

Abstract access 

Asia, Latin America, Northern America
Brazil, Canada, China, Republic of Korea
  • share
0 comments.