Articles tagged as "Netherlands"

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.

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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.

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

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

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

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

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

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

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

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

Abstract

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

Abstract  Full-text [free] access

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

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

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

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

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

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

Abstract

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

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

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

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

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

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

Abstract  Full-text [free] access

 

Africa, Asia, Europe, Northern America, Oceania
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How are we going to get to our prevention targets? Old tools, new tools and a more nuanced understanding of transmission dynamics.

Editor’s notes: By 2020, the Fast-Track strategy is aiming to reduce new HIV infections to 200 000 per year.  There is increasing recognition that if we are to succeed, we will need to do much more than simply putting people onto HIV treatment.  Despite the massive impact of ART on infectiousness, the decline in new infections at the community level is still not fast enough, even in countries like Botswana (see above) where 90-90-90 has almost been reached.  Renewed enthusiasm for primary prevention has also followed key trials of biomedical prevention tools including voluntary medical male circumcision and ARV-based prevention.  It is all too easy for us to forget the crucial role that condoms have played from the early days of the epidemic.  More recently, with HIV seen as a less terrifying infection, many programmes suffer from “condom fatigue”.  So it is good to see papers on the key importance of condoms as well as perspectives on how they are perceived by young men.

The magic of ARVs does not end with treatment.  We are finally moving to wider use of pre-exposure prophylaxis (PrEP).  There is no doubt that PrEP works when taken, but there are still plenty of questions for policy-makers about how to adopt it whole-heartedly into their national strategic plans and for financiers about how to pay for it.  Papers this month cover a range of experiences with PrEP from the US, where the huge majority of PrEP users still live, to Europe and Australia, where policies are finally moving towards wider use.  Long acting PrEP remains a key objective for many, as it might improve regular adherence, which has proved the Achilles’ heel of oral and topical PrEP in several of the large studies.

One of the ways to make PrEP most cost-effective is to ensure that it is available to people who are most likely to acquire HIV.  So the hope continues that phylogenetic analyses will allow more sophisticated understanding of the dynamics of the multiple overlapping networks of HIV transmission in communities.  Papers this month cover Australia and the PANGEA consortium of African research sites along with a cautionary comment about establishing the ethical framework for such studies, particularly among populations who are already subject to discrimination and criminalization.

When used correctly and consistently, condoms are highly effective not only to prevent HIV but also to prevent pregnancy and to prevent sexually transmitted infections.  Stover and colleagues have tried to capture all three benefits in one model.  They explore three potential scenarios for condom programming between now and 2030 in 81 countries that are priorities for family planning or HIV programmers or both.  The benefits of greater investment in condoms are huge.  In their most optimistic scenario, the authors suggest that if the entire gap between people who would like to use condoms and people who currently use them was filled (almost 11 billion condoms over the period), this could prevent up to 400 million unwanted pregnancies; 16.8 million new HIV infections and more than 700 million sexually transmitted infections.  The costs are quite modest, and at $115 per DALY averted this is an investment that everyone should support.  There are of course limitations in such a broad brush model, but it provides an excellent starting point.

The challenges in provision of condoms to young people go well beyond the cost and effectiveness considerations that underpin the previous analysis.  In an interesting qualitative study in South Africa, de Bruin and Panday-Soobrayan report their findings from focus group discussions with learners in 33 public schools.  Most of the learners were not in favour of provision of condoms at school, although they were keen on more youth friendly sexual and reproductive health and rights services within the public sector.  Many thought that provision of condoms would lead to earlier and more frequent sexual contacts, despite considerable experience showing that this is not the case in other settings.

Multiple trials have shown that PrEP is extremely effective when it is used consistently and correctly.  Many countries in all continents are now beginning to work out where it fits within their combination prevention package.  To date, the large majority of PrEP users are in the United States of America (USA), where more than 140 000 people have started.  It is much harder to measure how many are still taking it regularly.  Patel and colleagues analysed utilization at three months after the initial prescription of PrEP in three major PrEP clinics in three states in the USA.  18% of the 201 people (90% male) seen at baseline did not use their PrEP and this was strongly predicted by insurance status, with around a four-fold risk of dropping out among those who were not insured.  Although the numbers are small, this is an important study.  The authors suggest that increased insurance cover might make PrEP have a greater impact.  More broadly it raises the challenge that PrEP is often needed most by people least able to access it.  This will be a real challenge in countries where people most at risk, such as gay men and other men who have sex with men and sex workers, are criminalized or discriminated against in many health care settings.

In Australia, PrEP has been provided through large demonstration projects while awaiting decisions about how to include it in routine practice.  Lal and colleagues report results from 114 (one transgender woman, the rest male) people taking PrEP in the Victorian PrEP Demonstration project.  Participants have to pay an equivalent of an insurance co-payment, in order to make the situation more like the “real world”.  The participants were recruited because they were at high risk of HIV engaging in condomless anal sex with partners who were known to be living with HIV or of unknown status.  Adherence to PrEP was excellent as measured by a variety of reported and biological measures.  They observed one seroconversion in a man with exposure two weeks before starting PrEP who was already in the process of seroconverting and whose virus was found to be resistant to emtricitabine.  The only other seroconversion occurred in someone who had not yet started PrEP.  The authors found a substantial increase in rates of gonorrhoea and chlamydia once participants were “stable” on PrEP after three months.  There was also a significant reduction in condom use with both regular and casual partners.  This is one of the first studies to document important risk compensation among PrEP users.  Of course, preventing HIV is a huge benefit that generally outweighs the harms of additional treatment for sexually transmitted infections.  However, the study emphasizes the importance of enhancing sexual health services alongside PrEP and reminds us that people most at risk of HIV are also at high risk of other infections (and also of pregnancy in the context of heterosexual transmission.)  If PrEP is integrated within a broad sexual health service, there could be considerable synergistic benefits.

Gay men and men who have sex with men who enrolled in the PrEP demonstration project in Amsterdam also had high concomitant rates of hepatitis C virus (HCV).  Hoorenborg and colleagues found that around 5% of the 375 men enrolled in the project were co-infected.  The HCV found among these men were genetically similar to those circulating in the population of gay men and other men who have sex with men living with HIV, and more distinct from HCV from other risk groups.  This is good evidence that HCV and HIV both circulate in this population, and emphasizes once again the need for more integrated services, including hepatitis screening.

The ÉCLAIR study is a phase 2a trial of cabotegravir injections in healthy HIV-negative male volunteers.  As noted, adherence is a major challenge in many PrEP trials; although notably less of a problem when people choose to take PrEP in demonstration projects.  It is hoped that cabotegravir could be the first long acting PrEP.  Markowitz and colleagues presented the results of this study at CROI 2017.  The authors point out that although the injections are painful, many men stated that they would be happy to continue if the injections were effective.  No serious safety challenges emerged. The pharmacokinetics suggests that a dose given more frequently will be needed – and subsequent trials will use a two monthly regimen. 

One group for whom PrEP has been recommended by WHO for some years are serodiscordant couples (SDCs).  The Partners PrEP study, which forms one of the cornerstones for the evidence that PrEP works for both men and women, was conducted in SDCs.  The idea is to protect the HIV-negative partner from infection until such time as the partner living with HIV has been on ART consistently and suppressed their viral load.  So a study from the Centers for Disease Control USA is relevant to discussions of PrEP.  Crepaz and colleagues found that around 6000 new HIV infections occur each year in the USA among men and women having heterosexual sex and are aware that their partner is living with HIV.  They point out that viral suppression is achieved by only around 50% of heterosexuals living with HIV and that an additional proportion does not know their HIV status.  So the importance of HIV testing, and of focusing efforts on serodiscordant couples is clear.  Such efforts include both improving HIV treatment effectiveness, and providing a range of prevention choices including PrEP until viral suppression is achieved.

While the study above used traditional epidemiological surveillance reports, phylogenetics may provide additional insights into the dynamics of transmission.  In Australia, where notifications with HIV are rising steadily,  Castley and colleagues have examined the sequence data from almost 5000 viruses collected across the country from 2005-2012.  This sample is drawn from around 1200 new HIV infections per year (and around 27 000 people living with HIV).  The sample is not random, but reflects samples that were sent for sequencing to determine drug resistance.  Around one quarter of sequences are found in tight clusters (pairs, triplets or more) with other sequences, making it likely that they are closely connected by transmission.  Of course, all HIV sequences have been transmitted, so a longer time period and complete sampling would be expected to give a much higher proportion in clusters.  Indeed the more recent samples are around twice as likely to be in clusters as those collected at the start of the time period. Nonetheless, the large sample and the time period of collection allows some clear observations to be made.  In all states, the proportion of non-B subtypes is increasing, which must relate to travel and migration to and from Asia and Africa.  There is little evidence that the C subtypes (originally from Africa) are found in all male clusters suggesting little spill over into the community of gay men and other men having sex with men.  Larger clusters are more common among younger, all male networks. Like most molecular epidemiological studies, there are a small number of large clusters which represent highly active transmission.  These clusters are also most likely to be all male.  Taken together, the results suggest that the steady rise in notifications in Australia is probably due to increasing migration and travel and to ongoing active transmission networks among young gay men.  The challenge is to turn this sort of analysis into clear policy recommendations that can improve HIV prevention.

UNAIDS joined an interesting meeting on the ethics of phylogenetic studies in Africa organised by the PANGEA consortium.  Many of the issues discussed are also covered in a comment by Cohen on the importance of thinking through the risks inherent in these studies.  A key issue is to ensure that systems are reinforced to monitor any unexpected harms and to establish mitigation strategies to minimize them.  The challenges are not necessarily different to traditional epidemiological studies which may highlight networks and locations of groups that are criminalized or discriminated against.  In community consultations, prior to agreeing to go forward with phylogenetic studies, some potential participants even say that they would be keen to “know who infected them” in order to punish them.  This is clearly NOT the aim of such studies and emphasizes the importance of clear information about the limitations of the techniques which cannot usually rule out the possibility of additional links in the transmission chain.  Issues of anonymised information and what to do if clinically relevant results such as drug resistance mutations are uncovered as incidental findings also need to be discussed.

Furthermore, Ratmann and colleagues, reporting on the first 4000 sequences from the PANGEA consortium (largely from the Rakai project in Uganda), also emphasize some of the technical challenges that may lead to erroneous results in creating phylogenies.  There is little doubt that as the cost of sequencing falls and as the technologies and software become increasingly straightforward, we will see more and more studies of sequence data.  It is likely that analysis of these data will lead to more nuanced approaches to HIV prevention, particularly as the overall incidence falls, and sharper tools are needed to dissect the pathways of ongoing transmission.

The case for investing in the male condom

Stover J, Rosen JE, Carvalho MN, Korenromp EL, Friedman HS, Cogan M, Deperthes B. PLoS One. 2017 May 16;12(5):e0177108. doi: 10.1371/journal.pone.0177108. eCollection 2017.

When used correctly and consistently, the male condom offers triple protection from unintended pregnancy and the transmission of sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). However, with health funding levels stagnant or falling, it is important to understand the cost and health impact associated with prevention technologies. This study is one of the first to attempt to quantify the cost and combined health impact of condom use, as a means to prevent unwanted pregnancy and to prevent transmission of STIs including HIV. This paper describes the analysis to make the case for investment in the male condom, including the cost, impact and cost-effectiveness by three scenarios (low in which 2015 condom use levels are maintained; medium in which condom use trends are used to predict condom use from 2016-2030; and high in which condom use is scaled up, as part of a package of contraceptives, to meet all unmet need for family planning by 2030 and to 90% for HIV and STI prevention by 2016) for 81 countries from 2015-2030. An annual gap between current and desired use of 10.9 billion condoms was identified (4.6 billion for family planning and 6.3 billion for HIV and STIs). Under a high scenario that completely reduces that gap between current and desired use of 10.9 billion condoms, we found that by 2030 countries could avert 240 million DALYs. The additional cost in the 81 countries through 2030 under the medium scenario is $1.9 billion, and $27.5 billion under the high scenario. Through 2030, the cost-effectiveness ratios are $304 per DALY averted for the medium and $115 per DALY averted for the high scenario. Under the three scenarios described above, our analysis demonstrates the cost-effectiveness of the male condom in preventing unintended pregnancy and HIV and STI new infections. Policy makers should increase budgets for condom programming to increase the health return on investment of scarce resources.

Abstract  Full-text [free] access

Learners' perspectives on the provision of condoms in South African public schools.

de Bruin WE, Panday-Soobrayan S. AIDS care. 2017 May 16:1-4. doi: 10.1080/09540121.2017.1327647. [Epub ahead of print]

A stubborn health challenge for learners in South African public schools concerns sexual and reproductive health and rights (SRHR). In 2015, the Department of Basic Education (DBE) proposed the provision of condoms and SRHR-services to learners in schools. This study aimed to contribute to the finalisation and implementation of DBE's policy by exploring learners' perspectives on the provision of condoms and SRHR-services in schools. Sixteen focus group discussions were conducted with learners (n = 116) from 33 public schools, to assess their attitudes, social influences, and needs and desires regarding condom provision and SRHR-services in schools. The majority of learners did not support condom provision in schools as they feared that it may increase sexual activity. Contrarily, they supported the provision of other SRHR-services as clinics fail to offer youth-friendly services. Learners' sexual behaviour and access to SRHR-services are strongly determined by their social environment, including traditional norms and values, and social-pressure from peers and adults. Learners' most pressing needs and desires to access condoms and SRHR-services in school concerned respect, privacy and confidentiality of such service provision. Implementation of DBE's policy must be preceded by an evidence-informed advocacy campaign to debunk myths about the risk of increased sexual activity, to advocate for why such services are needed, to shift societal norms towards open discussion of adolescent SRHR and to grapple with the juxtaposition of being legally empowered but socially inhibited to protect oneself from HIV, STIs and early pregnancy. Provision of condoms and other SRHR-services in schools must be sensitive to learners' privacy and confidentiality to minimise stigma and discrimination.

Abstract  Full-text [free] access

Impact of insurance coverage on utilization of pre-exposure prophylaxis for HIV prevention

Patel RR, Mena L, Nunn A, McBride T, Harrison LC, Oldenburg CE, Liu J, Mayer KH, Chan PA.  PLoS One. 2017 May 30;12(5):e0178737 . doi: 10.1371/journal.pone.0178737. eCollection 2017.

Pre-exposure prophylaxis (PrEP) can reduce U.S. HIV incidence. We assessed insurance coverage and its association with PrEP utilization. We reviewed patient data at three PrEP clinics (Jackson, Mississippi; St. Louis, Missouri; Providence, Rhode Island) from 2014-2015. The outcome, PrEP utilization, was defined as patient PrEP use at three months. Multivariable logistic regression was performed to determine the association between insurance coverage and PrEP utilization. Of 201 patients (Jackson: 34%; St. Louis: 28%; Providence: 28%), 91% were male, 51% were White, median age was 29 years, and 21% were uninsured; 82% of patients reported taking PrEP at three months. Insurance coverage was significantly associated with PrEP utilization. After adjusting for Medicaid-expansion and individual socio-demographics, insured patients were four times as likely to use PrEP services compared to the uninsured (OR: 4.49, 95% CI: 1.68-12.01; p = 0.003). Disparities in insurance coverage are important considerations in implementation programs and may impede PrEP utilization.

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Medication adherence, condom use and sexually transmitted infections in Australian PrEP users: interim results from the Victorian PrEP demonstration project

Lal L, Audsley J, Murphy D, Fairley CK, Stoove M, Roth N, Moore R, Tee BK, Puratmaja N, Anderson PL, Leslie D, Grant RM, De Wit J, Wright E; VicPrEP Study Team. AIDS. 2017 May 1 doi: 10.1097/QAD.0000000000001519. [Epub ahead of print]

Objective: HIV Pre-exposure prophylaxis (PrEP) decreases risk of HIV acquisition however its efficacy is closely dependent on adherence. There is also concern that the preventive effect of PrEP may be offset by risk compensation, notably an increase in condomless anal sex.

Design: Multi-site, open-label demonstration study that recruited people at current or recent risk of HIV infection in Melbourne, Australia.

Methods: Participants were recruited from three general practice clinics and one sexual health clinic in Melbourne and consented to take daily tenofovir/emtricitabine for 30 months. Sexual practice data, HIV and sexually transmitted infection (STI) test results were collected at baseline and 3-monthly during follow up. PrEP adherence was evaluated by self-report at clinical visits, online surveys, refill-based assessments and dried blood spot (DBS) testing. We present a 12-month interim analysis.

Results: 114 people were recruited. We observed a significant decline in condom use which occurred concomitantly with a significant increase in STIs over the first 12 months of PrEP. Incidence (per 100PY) of any STI was 43.2 and 119.8 at m0-3 and M3-12, respectively (IRR 2.77 (1.52, 5.56)). Adherence to PrEP medication was high by all measures, including six month TDF-FTC levels in DBS.

Conclusions: We found significant reduction in condom use and an increase STIs over the first 12 months of follow-up. High medication adherence rates coupled with a decline in condom use and a rise in STIs, suggests that prevention, early detection and treatment of STIs is a chief research priority in the current era of HIV PrEP.

Abstract

Men who have sex with men starting pre-exposure prophylaxis (PrEP) are at risk of HCV infection: evidence from the Amsterdam PrEP study

Hoornenborg E, Achterbergh RC, Van Der Loeff MF, Davidovich U, Hogewoning A, de Vries HJ, Schinkel J, Prins M, Laar TJWV; Amsterdam PrEP Project team in the HIV Transmission Elimination AMsterdam Initiative, MOSAIC study group. AIDS. 2017 May 1. doi: 10.1097/QAD.0000000000001522. [Epub ahead of print].

Objectives and Design: Hepatitis C virus (HCV) has been recognised as an emerging sexually transmitted infection (STI) among HIV-positive men who have sex with men (MSM). However, HIV-negative MSM at high risk for HIV might also be at increased risk for HCV. We studied the HCV prevalence in HIV-negative MSM who start pre-exposure prophylaxis (PrEP) in Amsterdam. Phylogenetic analysis was used to compare HCV strains obtained from HIV-negative and HIV-positive MSM.

Methods: At enrolment in the Amsterdam PrEP (AMPrEP) demonstration project, HIV-negative MSM were tested for the presence of HCV antibodies and HCV RNA. If positive for HCV RNA, an HCV NS5B gene fragment (709 bp) was sequenced and compared with HCV isolates from HIV-positive MSM (n = 223) and risk groups other than MSM (n = 153), using phylogenetic analysis.

Results: Of 375 HIV-negative MSM enrolled in AMPrEP, 18 (4.8%, 95%CI 2.9%-7.5%) of participants were anti-HCV and/or HCV RNA positive at enrolment; 15/18 (83%) had detectable HCV RNA. HCV genotyping showed genotype 1a (73%), 4d (20%) and 2b (7%). All HCV-positive MSM starting PrEP were part of MSM-specific HCV clusters containing MSM with and without HIV.

Conclusion: HCV prevalence among HIV-negative MSM who started PrEP was higher than previously reported. All HIV-negative HCV-positive MSM were infected with HCV strains already circulating among HIV-positive MSM. The increasing overlap between sexual networks of HIV-positive and HIV-negative MSM might result in an expanding HCV-epidemic irrespective of HIV-status. Hence, routine HCV testing should be offered to MSM at high risk for HIV, especially for those enrolling in PrEP programs.

Abstract

Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial.

Markowitz M, Frank I, Grant RM, Mayer KH, Elion R, Goldstein D, Fisher C, Sobieszczyk ME, Gallant JE, Van Tieu H, Weinberg W, . Margolis DA, Hudson KJ, Stancil BS, Ford SL, Patel P, Gould E, Rinehart AR, Smith KY, Spreen WR. Lancet HIV. 2017 May 22. pii: S2352-3018(17)30068-1. doi: 10.1016/S2352-3018(17)30068-1. [Epub ahead of print]

Background: Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection.

Methods: We did this multicentre, double-blind, randomised, placebo-controlled, phase 2a trial at ten sites in the USA. Healthy men (aged 18-65 years) deemed not at high risk of acquiring HIV-1 at screening were randomly assigned (5:1), via computer-generated central randomisation schedules, to receive cabotegravir or placebo. Participants received oral cabotegravir 30 mg tablets or matching placebo once daily during a 4 week oral lead-in phase, followed by a 1 week washout period and, after safety assessment, three intramuscular injections of long-acting cabotegravir 800 mg or saline placebo at 12 week intervals. Study site staff and participants were masked to treatment assignment from enrolment through week 41 (time of the last injection). The primary endpoint was safety and tolerability from the first injection (week 5) to 12 weeks after the last injection. We did analysis in the safety population, defined as all individuals enrolled in the study who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov identifier, NCT02076178.

Findings: Between March 27, 2014, and Feb 23, 2016, we randomly assigned 127 participants to receive cabotegravir (n=106) or placebo (n=21); 126 (99%) participants comprised the safety population. Most participants were men who have sex with men (MSM; n=106 [83%]) and white (n=71 [56%]). 87 (82%) participants in the cabotegravir group and 20 (95%) participants in the placebo group completed the injection phase. Adverse events (n=7 [7%]) and injection intolerability (n=4 [4%]) were the main reasons for withdrawal in the cabotegravir group. The frequency of grade 2 or higher adverse events was higher in participants in the long-acting cabotegravir group (n=75 [80%]) than in those in the placebo group (n=10 [48%]; p=0·0049), mostly due to injection-site pain (n=55 [59%]). No significant differences were noted in concomitant medications, laboratory abnormalities, electrocardiogram, and vital sign assessments. Geometric mean trough plasma concentrations were 0·302 μg/mL (95% CI 0·237-0·385), 0·331 μg/mL (0·253-0·435), and 0·387 μg/mL (0·296-0·505) for injections one, two, and three, respectively, indicating lower than predicted exposure. The geometric mean apparent terminal phase half-life estimated after the third injection was 40 days. Two (2%) MSM acquired HIV-1 infection, one in the placebo group during the injection phase and one in the cabotegravir group 24 weeks after the final injection when cabotegravir exposure was well below the protein-binding-adjusted 90% inhibitory concentration.

Interpretation: Despite high incidence of transient, mild-to-moderate injection-site reactions, long-acting cabotegravir was well tolerated with an acceptable safety profile. Pharmacokinetic data suggest that 800 mg administered every 12 weeks is a suboptimal regimen; alternative dosing strategies are being investigated. Our findings support further investigation of long-acting injectable cabotegravir as an alternative to orally administered pre-exposure prophylaxis regimens.

Abstract

Examination of HIV infection through heterosexual contact with partners who are known to be HIV infected in the United States, 2010-2015

Crepaz N, Dong B, Chen M, Hall I. AIDS. 2017 Jul 17;31(11):1641-1644. doi: 10.1097/QAD.0000000000001526.

Using data from the National HIV Surveillance System, we examined HIV infections diagnosed between 2010 and 2015 attributed to heterosexual contact with partners previously known to be HIV infected. More than four in 10 HIV infections among heterosexual males and five in 10 HIV infections among heterosexual women were attributed to this group. Findings may inform the prioritization of prevention and care efforts and resource allocation modeling for reducing new HIV infection among discordant partnerships.

Abstract

A national study of the molecular epidemiology of HIV-1 in Australia 2005–2012

Castley A, Sawleshwarkar S, Varma R, Herring B, Thapa K, Dwyer D, Chibo D, Nguyen N, Hawke K, Ratcliff R, Garsia R, Kelleher A, Nolan D; Australian Molecular Epidemiology Network-HIV (AMEN-HIV).. PLoS One. 2017 May 10;12(5):e0170601. doi: 10.1371/journal.pone.0170601. eCollection 2017.

Introduction: Rates of new HIV-1 diagnoses are increasing in Australia, with evidence of an increasing proportion of non-B HIV-1 subtypes reflecting a growing impact of migration and travel. The present study aims to define HIV-1 subtype diversity patterns and investigate possible HIV-1 transmission networks within Australia.

Methods: The Australian Molecular Epidemiology Network (AMEN) HIV collaborating sites in Western Australia, South Australia, Victoria, Queensland and western Sydney (New South Wales), provided baseline HIV-1 partial pol sequence, age and gender information for 4873 patients who had genotypes performed during 2005-2012. HIV-1 phylogenetic analyses utilised MEGA V6, with a stringent classification of transmission pairs or clusters (bootstrap ≥98%, genetic distance ≤1.5% from at least one other sequence in the cluster).

Results: HIV-1 subtype B represented 74.5% of the 4873 sequences (WA 59%, SA 68.4%, w-Syd 73.8%, Vic 75.6%, Qld 82.1%), with similar proportion of transmission pairs and clusters found in the B and non-B cohorts (23% vs 24.5% of sequences, p = 0.3). Significantly more subtype B clusters were comprised of ≥3 sequences compared with non-B clusters (45.0% vs 24.0%, p = 0.021) and significantly more subtype B pairs and clusters were male-only (88% compared to 53% CRF01_AE and 17% subtype C clusters). Factors associated with being in a cluster of any size included; being sequenced in a more recent time period (p<0.001), being younger (p<0.001), being male (p = 0.023) and having a B subtype (p = 0.02). Being in a larger cluster (>3) was associated with being sequenced in a more recent time period (p = 0.05) and being male (p = 0.008).

Conclusion: This nationwide HIV-1 study of 4873 patient sequences highlights the increased diversity of HIV-1 subtypes within the Australian epidemic, as well as differences in transmission networks associated with these HIV-1 subtypes. These findings provide epidemiological insights not readily available using standard surveillance methods and can inform the development of effective public health strategies in the current paradigm of HIV prevention in Australia

Abstract  Full-text [free] access

HIV-1 full-genome phylogenetics of generalized epidemics in sub-Saharan Africa: impact of missing nucleotide characters in next-generation sequences.

Ratmann O, Wymant C, Colijn C, Danaviah S, Essex M, Frost SD, Gall A, Gaiseitsiwe S, Grabowski M, Gray R, Guindon S, von Haeseler A, Kaleebu P, Kendall M, Kozlov A, Manasa J, Minh BQ, Moyo S, Novitsky V, Nsubuga R, Pillay S, Quinn TC, Serwadda D, Ssemwanga D, Stamatakis A, Trifinopoulos J, Wawer M, Leigh Brown A, de Oliveira T, Kellam P, Pillay D, Fraser C.. AIDS Res Hum Retroviruses. 2017 May 25. doi: 10.1089/AID.2017.0061. [Epub ahead of print].

To characterize HIV-1 transmission dynamics in regions where the burden of HIV-1 is greatest, the 'Phylogenetics and Networks for Generalised HIV Epidemics in Africa' consortium (PANGEA-HIV) is sequencing full-genome viral isolates from across sub-Saharan Africa. We report the first 3985 PANGEA-HIV consensus sequences from four cohort sites (Rakai Community Cohort Study, n=2833; MRC/UVRI Uganda, n=701; Mochudi Prevention Project, n=359; Africa Health Research Institute Resistance Cohort, n=92). Next-generation sequencing success rates varied: more than 80% of the viral genome from the gag to the nef genes could be determined for all sequences from South Africa, 75% of sequences from Mochudi, 60% of sequences from MRC/UVRI Uganda, and 22% of sequences from Rakai. Partial sequencing failure was primarily associated with low viral load, increased for amplicons closer to the 3' end of the genome, was not associated with subtype diversity except HIV-1 subtype D, and remained significantly associated with sampling location after controlling for other factors. We assessed the impact of the missing data patterns in PANGEA-HIV sequences on phylogeny reconstruction in simulations. We found a threshold in terms of taxon sampling below which the patchy distribution of missing characters in next-generation sequences has an excess negative impact on the accuracy of HIV-1 phylogeny reconstruction, which is attributable to tree reconstruction artifacts that accumulate when branches in viral trees are long. The large number of PANGEA-HIV sequences provides unprecedented opportunities for evaluating HIV-1 transmission dynamics across sub-Saharan Africa and identifying prevention opportunities. Molecular epidemiological analyses of these data must proceed cautiously because sequence sampling remains below the identified threshold and a considerable negative impact of missing characters on phylogeny reconstruction is expected.

Abstract  Full-text [free] access

 

Africa, Asia, Europe, Northern America, Oceania
Afghanistan, Angola, Australia, Azerbaijan, Bangladesh, Benin, Bolivia, Botswana, Brazil, Burkina Faso, Burundi, Cambodia, Cameroon, Central African Republic, Chad, China, Comoros, Congo, Côte d'Ivoire, Democratic People's Republic of Korea, Democratic Republic of the Congo, Djibouti, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guatemala, Guinea, Guinea-Bissau, Haiti, India, Indonesia, Iran (Islamic Republic of), Iraq, Jamaica, Kenya, Kyrgyzstan, Lao People's Democratic Republic, Lesotho, Liberia, Madagascar, Malawi, Mauritania, Mexico, Morocco, Mozambique, Myanmar, Namibia, Nepal, Netherlands, Niger, Nigeria, Pakistan, Papua New Guinea, Peru, Philippines, Russian Federation, Rwanda, Sao Tome and Principe, Senegal, Sierra Leone, Solomon Islands, Somalia, South Africa, South Sudan, Sudan, Swaziland, Tajikistan, Togo, Turkmenistan, Uganda, Ukraine, United Republic of Tanzania, United States of America, Uzbekistan, Viet Nam, Yemen, Zambia, Zimbabwe
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Do people living with HIV live well with HIV in the era of antiretroviral therapy?

Editor’s notes: As treatment for HIV becomes increasingly widespread, and HIV-related deaths continue to decline, more and more attention is being paid to chronic non-communicable diseases and to the overall quality of life of people living with HIV.  However, despite 71% of people living with HIV in sub-Saharan Africa there is little research on the impact of illness and treatment on quality of life in the region.

Nyongesa and colleagues provide a fascinating mixed methods study, nested within a larger study of children and adolescents with HIV, which begins to formulate and validate a culturally appropriate tool to measure quality of life in the Swahili speaking population of coastal Kenya.  They used the functional assessment of HIV infection (FAHI) questionnaire as the starting point.  This is an HIV specific adaptation of a tool initially used among people with cancer and widely validated and studied in European and US based populations. 47 questions are used to assess HIV-specific quality of life in five domains: physical; emotional; functional and global well being; social; and cognitive functioning.

Following a scoping literature review, the authors used qualitative interviews with 38 participants living with HIV (largely female [27]) to explore their perceptions of the impact of HIV in the day-to-day life of people living with HIV in general. The issues raised overlapped with all the domains of FAHI except cognitive functioning, which the authors suggest is perhaps under-recognized when there are many competing stressors on people’s lives.  The participants then answered a draft version of the FAHI, which had been translated, back translated and reviewed in a group to ensure comprehension and relevance.  Following adaptation, the FAHI Swahili version was then administered to a sample of 103 randomly selected study participants living with HIV and on antiretroviral therapy from the same study site.  The sample was almost entirely female (94%) reflecting their availability at the parent study centre, which focussed on children and adolescents living with HIV.  Overall, the authors conclude that the new adaptation of the tool seems appropriate for further research studies on quality of life among people living with HIV on treatment in East Africa.  While the study provides a great example of a serious approach to develop, standardize and validate a culturally appropriate tool, the qualitative results also provide considerable insight into the many ways in which HIV affects these Kenyan’s lives beyond the purely medical.  Well worth reading the open access paper.

A study in Europe focussed specifically on the health-related domain of quality of life in Amsterdam.  Langebeek and colleagues used two tools that are well validated in European settings to assess physical and mental health related quality of life in 541 individuals living with HIV and 526 control participants without HIV.  HIV infection was clearly associated with worse quality of life, both mental and physical despite most participants being well controlled on ART.  As we might expect,  people who had multiple co-morbidities were less likely to have a good quality of life regardless of HIV status, but HIV remained an independent predictor of poor quality of life.  For mental health, HIV and younger age were both independently associated with less good quality of life.  The clear message is that we need to look beyond antiretroviral therapy and provide good holistic care including both mental and physical health services for people living with HIV, particularly as the population gets older.

A related study from Gonciulea and colleagues shows that among older men living with HIV, there is a significant increase in the risk of osteoporosis related fractures.  Bone demineralization is known to occur with risk factors such as age, sex, and low body mass index (BMI).However, increasingly studies are showing that HIV-related factors, such as antiretroviral medicines, ongoing viral replication and ongoing inflammation, are also potential risk factors. The authors used the multicenter AIDS cohort study to compare fracture incidence rates among 1221 men living with HIV and 1408 HIV-negative men.  Both cohorts were aged over 40 years.  As expected, fractures occurred more commonly as people got older, but the people living with HIV developed more fractures at an earlier age.  This study therefore reinforces the previous one, with the possibility to offer osteoporosis screening to men over the age of 50 who are living with HIV.

Petraglia and colleagues also explored the challenge of osteoporosis in people living with HIV.  Chronic obstructive pulmonary disease is known to be associated with low bone mineral density (BMD) and greater fracture risk in HIV negative smokers. In fact the finding of emphysema alone on CT imaging is a strong, independent predictor of osteoporosis in this group. We are beginning to observe obstructive lung disease as a common comorbidity in people living with HIV and emphysema has been shown to occur at an earlier age with less tobacco exposure in HIV positive smokers.  The authors therefore aimed to determine whether CT scans alone could predict who would turn out to have osteoporosis among people living with HIV.  As expected, they found that, among 164 people living with HIV, age; smoking and emphysema on CT scan were all associated with reduced BMD in the thoracic spine (estimated from the CT scan).  However, they also found that the emphysematous changes were an independent marker for this measure of osteoporosis regardless of age, sex, smoking, and use of antiretroviral medicines or steroids.  If a CT scan or lung function test suggests obstructive airways disease or emphysema, we should have a higher index of suspicion for osteoporosis among people living with HIV.

A mixed methods approach to adapting and evaluating the functional assessment of HIV infection (FAHI), Swahili version, for use with low literacy populations.

Nyongesa MK, Sigilai A, Hassan AS, Thoya J, Odhiambo R, Van de Vijver FJ, Newton CR, Abubakar A. PLoS One. 2017 Apr 5;12(4):e0175021. doi: 10.1371/journal.pone.0175021. eCollection 2017.

Background: Despite bearing the largest HIV-related burden, little is known of the Health-Related Quality of Life (HRQoL) among people living with HIV in sub-Saharan Africa. One of the factors contributing to this gap in knowledge is the lack of culturally adapted and validated measures of HRQoL that are relevant for this setting.

Aims: We set out to adapt the Functional Assessment of HIV Infection (FAHI) Questionnaire, an HIV-specific measure of HRQoL, and evaluate its internal consistency and validity.

Methods: The three phase mixed-methods study took place in a rural setting at the Kenyan Coast. Phase one involved a scoping review to describe the evidence base of the reliability and validity of FAHI as well as the geographical contexts in which it has been administered. Phase two involved in-depth interviews (n = 38) to explore the content validity, and initial piloting for face validation of the adapted FAHI. Phase three was quantitative (n = 103) and evaluated the internal consistency, convergent and construct validities of the adapted interviewer-administered questionnaire.

Results: In the first phase of the study, we identified 16 studies that have used the FAHI. Most (82%) were conducted in North America. Only seven (44%) of the reviewed studies reported on the psychometric properties of the FAHI. In the second phase, most of the participants (37 out of 38) reported satisfaction with word clarity and content coverage whereas 34 (89%) reported satisfaction with relevance of the items, confirming the face validity of the adapted questionnaire during initial piloting. Our participants indicated that HIV impacted on their physical, functional, emotional, and social wellbeing. Their responses overlapped with items in four of the five subscales of the FAHI Questionnaire establishing its content validity. In the third phase, the internal consistency of the scale was found to be satisfactory with subscale Cronbach's α ranging from 0.55 to 0.78. The construct and convergent validity of the tool were supported by acceptable factor loadings for most of the items on the respective sub-scales and confirmation of expected significant correlations of the FAHI subscale scores with scores of a measure of common mental disorders.

Conclusion: The adapted interviewer-administered Swahili version of FAHI questionnaire showed initial strong evidence of good psychometric properties with satisfactory internal consistency and acceptable validity (content, face, and convergent validity). It gives impetus for further validation work, especially construct validity, in similar settings before it can be used for research and clinical purposes in the entire East African region.

Abstract Full-text [free] access 

Impact of co-morbidity and aging on health-related quality of life in HIV-positive and HIV-negative individuals.

Langebeek N, Kooij KW, Wit FW, Stolte IG, Sprangers MAG, Reiss P, Nieuwkerk PT; AGEhIV Cohort Study Group. AIDS. 2017 Apr 19. doi: 10.1097/QAD.0000000000001511. [Epub ahead of print].

Background: HIV-infected individuals may be at risk for the premature onset of age-associated non-communicable co-morbidities. Being HIV-positive, having comorbidities and being of higher age may adversely impact health-related quality of life (HRQL). We investigated the possible contribution of HIV infection, co-morbidities, and age on HRQL and depression.

Methods: HIV-infected individuals and uninfected controls from the AGEhIV Cohort Study were screened for the presence of co-morbidities. They completed the Short Form 36-item Health Survey to assess HRQL and the nine-item Patient Health Questionnaire to assess depression. Linear and logistic regression were used to investigate to which extent co-morbidities, aging and HIV infection were independently associated with HRQL and depression.

Results: HIV-infected individuals (n = 541) reported significantly worse physical and mental HRQL and had a higher prevalence of depression than HIV-uninfected individuals (n = 526). A higher number of co-morbidities and HIV-positive status were each independently associated with worse physical HRQL, whereas HIV-positive status and younger age were independently associated with worse mental HRQL and more depression. The difference in physical HRQL between HIV-positive and HIV-negative individuals did not become greater with a higher number of co-morbidities or with higher age.

Conclusions: In a cohort of largely well-suppressed HIV-positive participants and HIV-negative controls, HIV-positive status was significantly and independently associated with worse physical and mental HRQL and with an increased likelihood of depression. Our finding that a higher number of co-morbidities was independently associated with worse physical HRQL reinforces the importance to optimize prevention and management of co-morbidities as the HIV-infected population continues to age.

Abstract access 

 An increased rate of fracture occurs a decade earlier in HIV+ compared to HIV- men in the Multicenter AIDS Cohort Study (MACS).

Gonciulea A, Wang R, Althoff KN, Palella FJ, Lake J, Kingsley LA, Brown TT. AIDS. 2017 Apr 3. doi: 10.1097/QAD.0000000000001493 [Epub ahead of print].

Objectives: To determine the incidence and age-related fracture risk among HIV-infected (HIV+) and uninfected men (HIV-). To evaluate factors independently associated with fracture risk.

Design: Prospective, multicenter cohort study of men with or at risk for HIV.

Methods: Outcome measures: 1) all fractures (excluding skull, face, digits) and 2) fragility fractures (vertebral column, femur, wrist, humerus) were collected semiannually in 1221 HIV+ and 1408 HIV- men ≥ age 40. Adjusted incident rate ratios (aIRR) with an interaction term for age (40-49, 50-59, ≥60 years) and HIV serostatus were estimated with Poisson regression models accounting for additional risk factors.

Results: Fracture incidence increased with age among both HIV+ and HIV- men. While there was no significant difference in fracture incidence by HIV serostatus among men aged 40-49 years, the HIV+ men aged 50-59 years had a significantly higher incidence of all fractures (aIRR = 2.06 [1.49, 2.84]) and fragility fractures (aIRR = 2.06 [1.21, 3.50]) compared with HIV- participants of similar age. HIV modified the effect of age on all fractures (p = 0.002) but did not significantly modify the effect for fragility fractures (p = 0.135). Hypertension increased the rate of all fractures by 32% after adjustment for covariates (aIRR = 1.32 [1.04, 1.69]).

Conclusions: Fracture incidence increased with age among HIV+ and HIV- men but was higher among HIV+ men. A significant increase in fracture incidence was found among 50-59-year-old HIV+ men, highlighting the importance of osteoporosis screening for HIV infected men above the age of 50.

Abstract access 

Emphysema is associated with thoracic vertebral bone attenuation on chest CT scan in HIV-infected individuals.

Petraglia A, Leader JK, Gingo M, Fitzpatrick M, Ries J, Kessinger C, Lucht L, Camp D, Morris A, Bon J. PLoS One. 2017 Apr 27;12(4):e0176719. doi: 10.1371/journal.pone.0176719. eCollection 2017.

Background: Age-related chronic diseases are prevalent in HIV-infected persons in the antiretroviral therapy (ART) era. Bone mineral density (BMD) loss and emphysema have separately been shown to occur at a younger age and with lesser risk exposure in HIV-infected compared to HIV-uninfected individuals. In non-HIV infected smokers, emphysema has been shown to independently predict low BMD. We hypothesized that emphysema would independently associate with thoracic vertebral bone attenuation, a surrogate for bone mineral density, in HIV-infected individuals.

Methods: Clinical, pulmonary function, and radiographic data were analyzed for 164 individuals from the University of Pittsburgh's HIV Lung Research Center cohort. Chest CT scans were used to quantify emphysema and compute Hounsfield Unit (HU) attenuation of the 4th, 7th, and 10th thoracic vertebrae. The association between mean HU attenuation values across the three vertebrae and radiographic emphysema, age, sex, body mass index (BMI), steroid use, viral load, CD4 count, and forced expiratory volume in the first second (FEV1) was assessed by univariate and multivariate analyses.

Results: In univariate analysis, mean HU attenuation decreased with increasing age (p<0.001), pack years (p = 0.047), and percent emphysema (p<0.001). In a multivariable model, including pack years, age, sex, ART and steroid use, greater emphysema was independently associated with this surrogate marker of BMD in HIV-infected individuals (p = 0.034).

Conclusions: The association of emphysema with thoracic bone attenuation in HIV-infected individuals is consistent with previous reports in non-HIV infected smokers. These findings suggest that emphysema should be considered a potential marker of osteoporosis risk in HIV-infected individuals.

Abstract Full-text [free] access 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Abstract access 

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

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

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

Abstract access 

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

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

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

Abstract access 

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

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

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

Abstract access 

Improvements in Spectrum's fit to program data tool.

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

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

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

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

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

Abstract access 

Analytical advances in the ex vivo challenge efficacy assay.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Abstract access 

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

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

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

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

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

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

Abstract access 

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

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

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

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

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

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

Abstract access 

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

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

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

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

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

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

Abstract access 

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

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

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

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

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

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

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

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

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

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

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

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

Design: Prospective observational study.

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

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

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

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Comorbidity, HIV Treatment
Africa, Asia, Europe, Northern America, Oceania
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Dolutegravir in the real world – more intolerance than first thought?

Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice.

de Boer MG, van den Berk GE, van Holten N, Oryszcyn JE, Dorama W, Moha DA, Brinkman K. AIDS. 2016 Nov 28;30(18):2831-2834.

Objective: Dolutegravir (DGV) is one of the preferred antiretroviral agents in first-line combination antiretroviral therapy (cART). Though considered to be a well tolerated drug, we aimed to determine the actual rate, timing and detailed motivation of stopping DGV in a real-life clinical setting.

Design: A cohort study including all patients who started DGV in two HIV treatment centers in The Netherlands.

Methods: All cART-naive and cART-experienced patients who had started DGV were identified from the institutional HIV databases. Clinical data, including motivation and timing of discontinuation of DGV, were extracted from the patient files. Factors that potentially influenced discontinuation of DGV were compared between patients who stopped or continued DGV by multivariate and Kaplan-Meier analyses.

Results: In total, 556 patients were included, of whom 102 (18.4%) were cART-naive at initiation of DGV. Median follow-up time was 225 days. Overall, in 85 patients (15.3%), DGV was stopped. In 76 patients (13.7%), this was due to intolerability. Insomnia and sleep disturbance (5.6%), gastrointestinal complaints (4.3%) and neuropsychiatric symptoms such as anxiety, psychosis and depression (4.3%) were the predominant reasons for switching DGV. In regimens that included abacavir, DGV was switched more frequently (adjusted relative risk 1.92, 95% confidence interval 1.09-3.38, P log-rank 0.01). No virologic failures were observed.

Conclusion: A relatively high rate of preliminary discontinuation of DGV due to intolerability was detected in our patient population. In particular, DGV was stopped more frequently if the regimen included abacavir. Multiple factors may explain these unexpected postmarketing observations, which warrant further investigation.

Abstract access  

Editor’s notes: The integrase inhibitor dolutegravir has been billed as a very important milestone in the treatment of HIV. Randomized controlled trials reported that not only was it a highly effective antiviral agent, but it also had a high barrier to resistance. Trial data also suggested an excellent safety profile. Trial participants experienced fewer side effects with dolutegravir use compared to many other drugs. For these reasons, dolutegravir is recommended as one of the preferred options for first-line treatment in European and United States treatment guidelines. In addition, it is increasingly becoming a key component in global efforts to expand access to HIV-positive people in low-income countries.

However, with increased use of dolutegravir beyond clinical trials, evidence is growing to suggest that the incidence of side effects is greater than trial data would predict. This study describes the two-year experience of a cohort spanning two medical centres in the Netherlands. It explores the rate and cause of discontinuation of dolutegravir-containing regimes in both antiretroviral therapy naïve and experienced individuals. Of 556 receiving a dolutegravir-containing regimen, just over 15% stopped its use over two years. Adverse effects were cited as the cause in a sizeable 13%. These rates of discontinuation are over five times higher than was reported from clinical trials. The predominant side effects were sleep disturbance and insomnia. Other reactions included gastrointestinal disturbances, anxiety, depression and general malaise. In terms of factors associated with increased risk of discontinuation, only the concomitant use of abacavir was identified.

These results do not detract from the importance of dolutegravir as an antiretroviral agent. Indeed, it is reassuring that in this cohort no virologic failure occurred as result of its discontinuation. The results instead highlight the need for caution concerning recommendations for dolutegravir as a universal first line agent until further data are accrued from real-world experience.

Europe
Netherlands
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Pre-exposure prophylaxis for HIV prevention is cost-effective in the Netherlands

Cost-effectiveness analysis of pre-exposure prophylaxis for HIV-1 prevention in the Netherlands: a mathematical modelling study.

Nichols BE, Boucher CA, van der Valk M, Rijnders BJ, van de Vijver DA. Lancet Infect Dis. 2016 Sep 22. pii: S1473-3099(16)30311-5. doi: 10.1016/S1473-3099(16)30311-5. [Epub ahead of print]

Background: Pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine prevents HIV infections among men who have sex with men (MSM). PrEP can be given on a daily or intermittent basis. Unfortunately, PrEP is not reimbursed in most European countries. Cost-effectiveness analyses of PrEP among MSM in Europe are absent but are key for decision makers to decide upon PrEP implementation.

Methods: We developed a deterministic mathematical model, calibrated to the well-defined Dutch HIV epidemic among MSM, to predict the effect and cost-effectiveness of PrEP. PrEP was targeted to 10% of highly sexually active Dutch MSM over the coming 40 years. Cost-effectiveness ratios were calculated to predict the cost-effectiveness of daily and on-demand PrEP. Cost-effectiveness ratios below euro20 000 were considered to be cost-effective in this analysis.

Findings: Within the context of a stable HIV epidemic, at 80% effectiveness and current PrEP pricing, PrEP can cost as much as euro11 000 (IQR 9400-14 100) per quality-adjusted life-year (QALY) gained when used daily, or as little as euro2000 (IQR 1300-3000) per QALY gained when used on demand. At 80% effectiveness, daily PrEP can be considered cost-saving if the price of PrEP is reduced by 70%, and on-demand PrEP can be considered cost-saving if the price is reduced by 30-40%.

Interpretation: PrEP for HIV prevention among MSM in the Netherlands is cost-effective. The use of PrEP is most cost-effective when the price of PrEP is reduced through on-demand use or through availability of generic PrEP, and can quickly be considered cost-saving.

Abstract access  

Editor’s notes: Evidence surrounding the clinical effectiveness of pre-exposure prophylaxis to prevent HIV infection has been building for years (see HIV This Month January 2016 and February 2015).  This article now adds to the evidence with indications that pre-exposure prophylaxis is also cost-effective in a European setting.

The authors use a deterministic mathematical model to represent the HIV epidemic in the Netherlands among gay men and other men who have sex with men. They estimate the cost and cost-effectiveness of two models of pre-exposure prophylaxis usage: a daily dosage, and an ‘on demand’ dosage.  Their base case analysis found that both usage models fall under a willingness-to-pay ratio of €20 000 per QALY gained over a 40-year time horizon, although the ‘on demand’ model was least expensive at only €2000 (IQR 1300–3000) per QALY gained.  The model reflected some uncertainty around the results. However, very few results from the sensitivity analysis indicated a cost-per-QALY ratio above €20 000. Several scenarios indicated that pre-exposure prophylaxis was cost-saving. 

Pre-exposure prophylaxis was approved by the European Medicines Agency in July 2016, however it is currently not reimbursed by most European governments. This paper provides important evidence to make a case in favour of recommending reimbursement. Although the willingness-to-pay threshold used (€20 000/QALY) does not have any formal recognition in the Netherlands, several independent analyses soliciting the Dutch society’s value of a QALY reflect values much higher than this. As noted in the comment accompanying this paper (Niessen and Jaffar), the potential cost of implementing pre-exposure prophylaxis on a large-scale could be higher than current budgetary priorities allow. Still, this is an important study adding to the mounting evidence that countries should begin to consider how pre-exposure prophylaxis can be made available to people at highest risk of HIV infection.  

Europe
Netherlands
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The negative health impacts of HIV-associated stigma

Examining the associations between HIV-related stigma and health outcomes in people living with HIV/AIDS: a series of meta-analyses.

Rueda S, Mitra S, Chen S, Gogolishvili D, Globerman J, Chambers L, Wilson M, Logie CH, Shi Q, Morassaei S, Rourke SB. BMJ Open. 2016 Jul 13;6(7):e011453. doi: 10.1136/bmjopen-2016-011453.

Objective: To conduct a systematic review and series of meta-analyses on the association between HIV-related stigma and health among people living with HIV.

Data sources: A structured search was conducted on 6 electronic databases for journal articles reporting associations between HIV-related stigma and health-related outcomes published between 1996 and 2013.

Study eligibility criteria: Controlled studies, cohort studies, case-control studies and cross-sectional studies in people living with HIV were considered for inclusion.

Outcome measures: Mental health (depressive symptoms, emotional and mental distress, anxiety), quality of life, physical health, social support, adherence to antiretroviral therapy, access to and usage of health/social services and risk behaviours.

Results: 64 studies were included in our meta-analyses. We found significant associations between HIV-related stigma and higher rates of depression, lower social support and lower levels of adherence to antiretroviral medications and access to and usage of health and social services. Weaker relationships were observed between HIV-related stigma and anxiety, quality of life, physical health, emotional and mental distress and sexual risk practices. While risk of bias assessments revealed overall good quality related to how HIV stigma and health outcomes were measured on the included studies, high risk of bias among individual studies was observed in terms of appropriate control for potential confounders. Additional research should focus on elucidating the mechanisms behind the negative relationship between stigma and health to better inform interventions to reduce the impact of stigma on the health and well-being of people with HIV.

Conclusions: This systematic review and series of meta-analyses support the notion that HIV-related stigma has a detrimental impact on a variety of health-related outcomes in people with HIV. This review can inform the development of multifaceted, intersectoral interventions to reduce the impact of HIV-related stigma on the health and well-being of people living with HIV.

Abstract  Full-text [free] access 

Editor’s notes: There is a growing body of research documenting the negative impact of stigma and discrimination on the health of people living with HIV. Stigma is associated with poorer mental health, including emotional distress, depression and reduced psychological functioning. It has also been linked to intermediate health outcomes such as seeking healthcare and adherence to antiretroviral therapy. This paper reports a comprehensive systematic review and meta-analyses summarising the published evidence on the relationship between HIV-associated stigma and a wide range of health outcomes, including intermediate health outcomes. Results illustrate associations between HIV-associated stigma and depressive symptoms, lower levels of social support, ART adherence and use of health services. However, the majority of studies in the review were cross-sectional and longitudinal studies are necessary to explore the complex relationship between these factors, including the role of moderating factors, such as coping strategies. In addition, more research is necessary from low- and middle-income countries given that much of the published research is from North America. Further, there is also a need to better understand the intersection of HIV-associated stigma with other types of stigma experienced by people living with HIV, including homophobia, racism and gender discrimination. 

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