Articles tagged as "Biomedical interventions and prevention tools"

CrAg screening needs strengthened implementation in South Africa

Evaluation of a public-sector, provider-initiated cryptococcal antigen screening and treatment program, western Cape, South Africa.

Vallabhaneni S, Longley N, Smith M, Smith R, Osler M, Kelly N, Cross A, Boulle A, Meintjes G, Govender NP. J Acquir Immune Defic Syndr. 2016 Feb 29. [Epub ahead of print]

Background: Screening for serum cryptococcal antigen (CrAg) may identify those at risk for disseminated cryptococcal disease (DCD), and pre-emptive fluconazole treatment may prevent progression to DCD. In August 2012, the Western Cape Province (WC), South Africa, adopted provider-initiated CrAg screening. We evaluated the implementation and effectiveness of this large-scale public-sector program during its first year, September 1, 2012-August 31, 2013.

Methods: We used data from the South African National Health Laboratory Service, WC provincial HIV program, and nationwide surveillance data for DCD. We assessed the proportion of eligible patients screened for CrAg (CrAg test done within 30 days of CD4 date) and the prevalence of CrAg positivity. Incidence of DCD among those screened was compared with those not screened.

Results: Of 4395 eligible patients, 26.6% (n=1170) were screened. The proportion of patients screened increased from 15.9% in September 2012 to 36.6% in August 2013. The prevalence of positive serum CrAg was 2.1%. Treatment data were available for 13 of 24 CrAg-positive patients; nine of 13 were treated with fluconazole. Nine (0.8%) incident cases of DCD occurred among the 1170 patients who were screened for CrAg vs. 49 (1.5%) incident cases among the 3225 patients not screened (p=0.07).

Conclusions: Relatively few eligible patients were screened under the WC provider-initiated CrAg screening program. Unscreened patients were nearly twice as likely to develop DCD. CrAg screening can reduce the burden of DCD, but needs to be implemented well. To improve screening rates, countries should consider laboratory-based reflexive screening when possible.

Abstract access  

Editor’s notes: Cryptococcus, a ubiquitous soil fungus, can cause cryptococcal meningitis (CM) or disseminated cryptococcal disease (DCD), which is often fatal among people with advanced HIV disease.  Despite antiretroviral therapy availability, CM is now the leading cause of adult meningitis in sub-Saharan Africa with a mortality of up to 70% at 12 weeks in low-income settings. Asymptomatic individuals with a positive serum cryptococcal antigen (CrAg) and low CD4 counts are at a high risk of progression to disease. Identifying these individuals and initiating pre-emptive treatment to reduce morbidity and mortality forms the rationale for the inclusion of CrAg screening in the South African national guidelines.

This evaluation of the public sector provider-initiated CrAg screening and treatment programme in the western Cape revealed disappointing coverage during the first year of implementation. A laboratory-based reflex testing strategy, where the CrAg test is performed in the laboratory on any blood sample with CD4<100 may improve screening coverage. But, this requires adequate laboratory infrastructure and needs to be paired with optimal uptake of pre-emptive fluconazole among people with a positive CrAg result. In this study, uptake of fluconazole was lower than desired with about a third of eligible patients, for whom records were available, lacking any evidence of receiving fluconazole. In addition, a significantly higher proportion of people screened started ART compared with people who were not screened. This might partly explain the reduced incidence of cryptococcal disease in the screened group. 

A stepped-wedge randomised trial evaluating CrAg screening in Uganda, presented at CROI 2016, found that one-third of persons with baseline CrAg titre of ≥1:160 died, despite receiving recommended pre-emptive fluconazole therapy. This suggests that semi-quantitative CrAg screening may be required to identify people at risk of death in whom more potent antifungal therapy may be necessary. The very high mortality in CrAg-positive patients despite antifungal therapy suggests that, for people at highest risk, CrAg screening should be implemented as part of a combined opportunistic infection screening and intervention package, including more intensive follow-up.

South Africa
  • share

Treating vaginal infections lowers risk of sexually transmitted bacterial infections

Periodic presumptive treatment for vaginal infections may reduce the incidence of bacterial sexually transmitted infections.

Balkus JE, Manhart LE, Lee J, Anzala O, Kimani J, Schwebke J, Shafi J, Rivers C, Kabare E, McClelland RS. J Infect Dis. 2016 Feb 4. pii: jiw043. [Epub ahead of print]

Background: Bacterial vaginosis (BV) may increase women's susceptibility to sexually transmitted infections (STIs). In a randomized trial of periodic presumptive treatment (PPT) to reduce vaginal infections, we observed a significant reduction in BV. We further assessed the intervention effect on incident Chlamydia trachomatis (CT), Neisseria gonorrhoeae (GC), and Mycoplasma genitalium (MG).

Methods: Non-pregnant, HIV-uninfected women from the US and Kenya received intravaginal metronidazole 750mg plus miconazole 200mg or placebo for 5 consecutive nights each month for 12 months. Genital fluid specimens were collected every other month. Poisson regression models were used to assess the intervention effect on STI acquisition.

Results: Of 234 women enrolled, 221 had specimens available for analysis. Incidence of any bacterial STI (CT, GC, or MG) was lower in the intervention arm compared to placebo (incidence rate ratio [IRR]=0.54, 95% CI 0.32-0.91). When assessed individually, reductions in STIs were similar but not statistically significant (CT:IRR=0.50, 95% CI 0.20-1.23; GC:IRR=0.56, 95% CI 0.19-1.67; MG:IRR=0.66, 95% CI 0.38-1.15).

Conclusions: In addition to reducing BV, this PPT intervention may also reduce women's bacterial STI risk. Because BV is highly prevalent, often persists, and frequently recurs after treatment, interventions that reduce BV over extended periods could play a role in decreasing STI incidence globally.

Abstract access

Editor’s notes: Increasing attention is being paid to the health of vaginal microbiota. Disruption of the vaginal microbiota i.e. dysbiosis, is thought to increase susceptibility to other sexually transmitted infections, including HIV. While considerable observational data support the hypothesis of vaginal dysbiosis being a risk factor for sexually transmitted infection, the hypothesis has not been confirmed through randomized control trials. Women in the programme arm of this randomized control trial were presumptively treated for bacterial vaginosis and vulvovaginal candidiasis on a monthly basis. Relative to the control arm, the women in the programme arm had approximately half the risk of infection by Chlamydia trachomatis, Neisseria gonorrhoea or Mycoplasma genitalium. The findings provide strong evidence for considering healthy vaginal flora as a protective factor from sexually transmitted bacterial infections. Further research must consider whether the protection extends to sexually transmitted viruses and protozoa, and for adolescents and women who are not of African heritage.

Africa, Northern America
Kenya, United States of America
  • share

We need to listen to people living with HIV who refuse or delay starting ART: lessons from Australia

On the margins of pharmaceutical citizenship: not taking HIV medication in the "treatment revolution" era.

Persson A, Newman CE, Mao L, de Wit J. Med Anthropol Q. 2016 Jan 12. doi: 10.1111/maq.12274. [Epub ahead of print]

With the expanding pharmaceuticalization of public health, anthropologists have begun to examine how biomedicine's promissory discourses of normalization and demarginalization give rise to new practices of and criteria for citizenship. Much of this work focuses on the biomedicine-citizenship nexus in less-developed, resource-poor contexts. But how do we understand this relationship in resource-rich settings where medicines are readily available, often affordable, and a highly commonplace response to illness? In particular, what does it mean to not use pharmaceuticals for a treatable infectious disease in this context? We are interested in these questions in relation to the recent push for early and universal treatment for HIV infection in Australia for the twin purposes of individual and community health. Drawing on Ecks's concept of pharmaceutical citizenship, we examine the implications for citizenship among people with HIV who refuse or delay recommended medication. We find that moral and normative expectations emerging in the new HIV "treatment revolution" have the capacity to both demarginalize and marginalize people with HIV.


Editor’s notes: Following the release of WHO ‘Guidelines on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV’ at the end of September 2015, there has been growing momentum to roll out treatment to all people living with HIV. This important paper highlights an important issue affecting the provision of antiretroviral therapy (ART) to all people living with HIV, regardless of CD4 cell count. Not everyone wants to start treatment promptly. The authors interviewed 27 people in Australia who had declined to start ART. Ten of these people had never used ART, while the remaining 17 had started and then stopped therapy. There were many reasons why these people chose not to start or continue with ART. These reasons included fears over side-effects and the commitment to life-long therapy. Some doubted that they needed ‘treatment’ because they were well. A few were sceptical about the efficacy of the drugs.  These reasons for delaying treatment are being echoed in research from other parts of the world. The authors of this paper note that if treatment is promoted as ‘normal’, then people who decline ART risk marginalisation for ‘not doing the right thing’. This, they suggest, is particularly the case in places where ART are readily and freely available, like Australia. The authors conclude by highlighting the importance of listening to people who do not want to start ART, and understanding their reservations, while ensuring they do not become marginalised.

  • share

Determinants of HIV prevention costs at scale in India

What determines HIV prevention costs at scale? Evidence from the Avahan programme in India.

Lépine A, Chandrashekar S, Shetty G, Vickerman P, Bradley J, Alary M, Moses S, Group CI, Vassall A. Health Econ. 2016 Feb;25 Suppl 1:67-82. doi: 10.1002/hec.3296. Epub 2016 Jan 14.

Expanding essential health services through non-government organisations (NGOs) is a central strategy for achieving universal health coverage in many low-income and middle-income countries. Human immunodeficiency virus (HIV) prevention services for key populations are commonly delivered through NGOs and have been demonstrated to be cost-effective and of substantial global public health importance. However, funding for HIV prevention remains scarce, and there are growing calls internationally to improve the efficiency of HIV prevention programmes as a key strategy to reach global HIV targets. To date, there is limited evidence on the determinants of costs of HIV prevention delivered through NGOs; and thus, policymakers have little guidance in how best to design programmes that are both effective and efficient. We collected economic costs from the Indian Avahan initiative, the largest HIV prevention project conducted globally, during the first 4 years of its implementation. We use a fixed-effect panel estimator and a random-intercept model to investigate the determinants of average cost. We find that programme design choices such as NGO scale, the extent of community involvement, the way in which support is offered to NGOs and how clinical services are organised substantially impact average cost in a grant-based payment setting.

Abstract  Full-text [free] access

Editor’s notes: This paper was published in the journal Health Economics, as part of a supplement on methods for economic evaluation in low-income and middle-income countries. The supplement eloquently summarizes the current state of the art for economic evaluation in these countries, providing a good background for readers who are less familiar with this field.  It also reflects challenges for the design, conduct, and use of economic evaluations in these settings and highlights some of the methodological innovations arising out of these challenges. 

This contribution reflects the importance of using cost functions when conducting economic evaluations of programmes that need to be scaled up. The authors present average costs for 138 non-governmental organisations providing HIV prevention services to key populations across four years in India, as part of the Avahan project. They find that scale is an important determinant of cost, with average costs falling as scale increases. They also find that community mobilization activities can reduce costs, potentially by encouraging uptake of other services.  Further, the way in which NGOs are supported can impact on costs. 

This article presents an important methodological step towards informing better decision-making and programme design. Understanding of cost drivers can also facilitate programme monitoring and resource allocation. This is one of the first studies fully powered to analyse the determinants of costs for NGO-delivered HIV prevention services.  The authors use a wealth of cost data which are not often available to researchers working in lower and middle income countries. As noted in the foreword for this supplement, further analysis of cost functions will be essential to inform future global and national-level decision-making in these countries. This will require investment in additional large-scale cost studies globally to generate data for this type of analysis.

  • share

Would an HIV vaccine be cost-effective? Possibly…

Exploring the potential health impact and cost-effectiveness of AIDS vaccine within a comprehensive HIV/AIDS response in low- and middle-income countries.

Harmon TM, Fisher KA, McGlynn MG, Stover J, Warren MJ, Teng Y, Naveke A. PLoS One. 2016 Jan 5;11(1):e0146387. doi: 10.1371/journal.pone.0146387. eCollection 2016.

Background: The Investment Framework Enhanced (IFE) proposed in 2013 by the Joint United Nations Programme on HIV/AIDS (UNAIDS) explored how maximizing existing interventions and adding emerging prevention options, including a vaccine, could further reduce new HIV infections and AIDS-related deaths in low- and middle-income countries (LMICs). This article describes additional modeling which looks more closely at the potential health impact and cost-effectiveness of AIDS vaccination in LMICs as part of UNAIDS IFE.

Methods: An epidemiological model was used to explore the potential impact of AIDS vaccination in LMICs in combination with other interventions through 2070. Assumptions were based on perspectives from research, vaccination and public health experts, as well as observations from other HIV/AIDS interventions and vaccination programs. Sensitivity analyses varied vaccine efficacy, duration of protection, coverage, and cost.

Results: If UNAIDS IFE goals were fully achieved, new annual HIV infections in LMICs would decline from 2.0 million in 2014 to 550 000 in 2070. A 70% efficacious vaccine introduced in 2027 with three doses, strong uptake and five years of protection would reduce annual new infections by 44% over the first decade, by 65% the first 25 years and by 78% to 122 000 in 2070. Vaccine impact would be much greater if the assumptions in UNAIDS IFE were not fully achieved. An AIDS vaccine would be cost-effective within a wide range of scenarios.

Interpretation: Even a modestly effective vaccine could contribute strongly to a sustainable response to HIV/AIDS and be cost-effective, even with optimistic assumptions about other interventions. Higher efficacy would provide even greater impact and cost-effectiveness, and would support broader access. Vaccine efficacy and cost per regimen are critical in achieving cost-effectiveness, with cost per regimen being particularly critical in low-income countries and at lower efficacy levels.

Abstract  Full-text [free] access

Editor’s notes: Developing a vaccine against HIV has been an enormous scientific challenge. However, an effective vaccine could revolutionise the field of HIV prevention. A late-stage clinical trial is set to start at the end of 2016 and there are currently more than 30 early-stage clinical studies to evaluate vaccine candidates. This paper has modelled the potential health impacts and cost-effectiveness of an HIV vaccine. They used primary assumptions from the Investment Framework Enhanced from UNAIDS, which models the impact of different prevention programmes in 24 countries accounting for some 85% of new HIV infections. They also carried out sensitivity analyses on vaccine efficacy, duration of protection, coverage and cost.

The authors found that a 70% efficacious vaccine introduced in 2027 with three doses, strong uptake would reduce annual new infections by 78% by 2070. The vaccine would be cost-effective under several scenarios explored. At a cost of $5 per dose, the vaccine would be cost-effective under all vaccine effectiveness scenarios (30%-90%).  At 70% effectiveness, the vaccine would also be cost-effectives in a range of costs per dose ($5-$20).

This study is valuable in that it presents the scenarios in which the introduction of a vaccine against HIV could potentially be cost-effective; it gives an idea of feasibility under certain conditions. However (and the authors acknowledge this) the model is based on assumptions for which there is scant evidence. So far clinical trials have only achieved a vaccine that is 30% effective so 70% effectiveness is still a pipe dream. Secondly, given the enormous amount of resources that may yet need to be invested to develop a vaccine, the cost per vaccine may be much higher than estimated here (even higher than the ‘very high price’ scenario). In addition, the cost of targeting the vaccine to most at risk populations is not discussed; this could also raise the cost per dose considerably.  A probabilistic sensitivity analysis as well as further threshold analysis in this area would be valuable exercises to follow up the findings in this paper. 

  • share

A pill for HIV prevention: to take when you need it

On-demand preexposure prophylaxis in men at high risk for HIV-1 infection.

Molina JM, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, Tremblay C, Le Gall JM, Cua E, Pasquet A, Raffi F, Pintado C, Chidiac C, Chas J, Charbonneau P, Delaugerre C, Suzan-Monti M, Loze B, Fonsart J, Peytavin G, Cheret A, Timsit J, Girard G, Lorente N, Preau M, Rooney JF, Wainberg MA, Thompson D, Rozenbaum W, Dore V, Marchand L, Simon MC, Etien N, Aboulker JP, Meyer L, Delfraissy JF, Group AIS. N Engl J Med. 2015 Dec 3;373(23):2237-46. doi: 10.1056/NEJMoa1506273. Epub 2015 Dec 1.

Background: Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen.

Methods: We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections.

Results: Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03).

Conclusions: The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events.

Abstract Full-text [free] access

Editor’s notes: The IPERGAY trial is the first trial to assess ‘on demand’ HIV pre-exposure prophylaxis (PrEP). It had a ‘take it when you need it’ approach, rather than a daily dosing approach where a pill is taken every day, regardless of sexual activity. In 2010, the iPrEx Trial of daily pills among gay men and other men who have sex with men reported a 42% relative reduction in HIV incidence. In participants with detectable drug in their blood (meaning that they had been taking the pills), the reduction was 92%. The IPERGAY researchers set out to prove or disprove the hypothesis that men would be more likely to take pills if pill-taking was associated with having sex. The hypothesis was that this might improve adherence and hence reduce the risk of HIV acquisition compared with daily dosing. Participants were randomly assigned to take a dose of two pills of TDF/FTC (tenofovir disoproxil fumarate/emtricitabine) or placebo with food between two and 24 hours before sex. A third pill was taken 24 hours after sex and a fourth pill 24 hours after that. If they continued to be sexually active, they were told to take one pill a day while sexually active and then the two post-exposure doses 24 hours apart. When the striking results of the PROUD trial in the United Kingdom, among gay men and other men who have sex with men, were made public [see HIV This Month February 2015], IPERGAY’s Data Safety and Monitoring Board (DSMB) asked for an unblinded interim analysis of the IPERGAY data. The results were so convincing (an 86% relative risk reduction) that the DSMB recommended that the trial be unblinded so that men in the placebo arm could be offered active drug. The next question was whether this highly effective preventive measure could be made available outside the trial setting. The Food and Drug Administration of the United States of America had approved TDF/FTC for HIV PrEP in 2012 but no country had followed suit. On November 23, 2015, France’s Minister for Social Affairs, Health, and Women’s Rights announced a temporary recommendation for the use of TDF/FTC HIV prophylaxis, opening the way to the authorisation of PrEP in other European countries. Before any other European country responded, South Africa’s Medicines Control Council announced on December 3, 2015 its approval of the fixed-dose combination of TDF/FTC for pre-exposure prophylaxis of HIV. Kenya’s Pharmacy & Poisons Board also approved once-daily use of TDF/FTC for HIV prevention on December 23, 2015. The scientific evidence has been building for years. Clearly it is time to act now to make this highly effective HIV prevention choice available to people at highest risk of HIV exposure.

Europe, Northern America
Canada, France
  • share

Long-acting PrEP might offer a solution to the challenges of adherence

Potential clinical and economic value of long-acting preexposure prophylaxis for South African women at high-risk for HIV infection.

Walensky RP, Jacobsen MM, Bekker LG, Parker RA, Wood R, Resch SC, Horstman NK, Freedberg KA, Paltiel AD. J Infect Dis. 2015 Dec 17. pii: jiv523. [Epub ahead of print]

Background: For young South African women at risk for human immunodeficiency virus (HIV) infection, preexposure prophylaxis (PrEP) is one of the few effective prevention options available. Long-acting injectable PrEP, which is in development, may be associated with greater adherence, compared with that for existing standard oral PrEP formulations, but its likely clinical benefits and additional costs are unknown.

Methods: Using a computer simulation, we compared the following 3 PrEP strategies: no PrEP, standard PrEP (effectiveness, 62%; cost per patient, $150/year), and long-acting PrEP (effectiveness, 75%; cost per patient, $220/year) in South African women at high risk for HIV infection (incidence of HIV infection, 5%/year). We examined the sensitivity of the strategies to changes in key input parameters among several outcome measures, including deaths averted and program cost over a 5-year period; lifetime HIV infection risk, survival rate, and program cost and cost-effectiveness; and budget impact.

Results: Compared with no PrEP, standard PrEP and long-acting PrEP cost $580 and $870 more per woman, respectively, and averted 15 and 16 deaths per 1000 women at high risk for infection, respectively, over 5 years. Measured on a lifetime basis, both standard PrEP and long-acting PrEP were cost saving, compared with no PrEP. Compared with standard PrEP, long-acting PrEP was very cost-effective ($150/life-year saved) except under the most pessimistic assumptions. Over 5 years, long-acting PrEP cost $1.6 billion when provided to 50% of eligible women.

Conclusions: Currently available standard PrEP is a cost-saving intervention whose delivery should be expanded and optimized. Long-acting PrEP will likely be a very cost-effective improvement over standard PrEP but may require novel financing mechanisms that bring short-term fiscal planning efforts into closer alignment with longer-term societal objectives.

Abstract  Full-text [free] access

Editor’s notes: Standard oral pre-exposure prophylaxis (PrEP) is effective in preventing HIV and is one of the few proven prevention options available to young women at risk of HIV. However, daily adherence is key and trials have illustrated problems with adherence in several populations. Development of long-acting injectable formulations of PrEP may provide an option that does not require daily adherence to pills. In anticipation of new formulations of PrEP, this study modelled the potential clinical benefits, additional cost, cost-effectiveness and budget impact of existing and novel PrEP strategies. Given that the effectiveness and cost of long-acting PrEP is unknown, sensitivity analyses were conducted to look at varied effectiveness, HIV infection incidence, age at PrEP discontinuation and programmatic cost. The results suggest that long-acting PrEP is likely to be more clinically and cost-effective than standard oral PrEP. However, it will place an even greater strain on existing HIV prevention budgets. In addition to the research necessary to establish its clinical effectiveness, efforts to develop novel financing mechanisms are also required.         

South Africa
  • share

Effective pre-conception ART eliminates mother-to-child transmission

No perinatal hiv-1 transmission from women with effective antiretroviral therapy starting before conception.

Mandelbrot L, Tubiana R, Le Chenadec J, Dollfus C, Faye A, Pannier E, Matheron S, Khuong MA, Garrait V, Reliquet V, Devidas A, Berrebi A, Allisy C, Elleau C, Arvieux C, Rouzioux C, Warszawski J, Blanche S, Group A-ES. Clin Infect Dis. 2015 Dec 1;61(11):1715-25. doi: 10.1093/cid/civ578. Epub 2015 Jul 21.

Background: The efficacy of preventing perinatal transmission (PT) of human immunodeficiency virus type 1 (HIV-1) depends on both viral load (VL) and treatment duration. The objective of this study was to determine whether initiating highly active antiretroviral therapy (ART) before conception has the potential to eliminate PT.

Methods: A total of 8075 HIV-infected mother/infant pairs included from 2000 to 2011 in the national prospective multicenter French Perinatal Cohort (ANRS-EPF) received ART, delivered live-born children with determined HIV infection status, and did not breastfeed. PT was analyzed according to maternal VL at delivery and timing of ART initiation.

Results: The overall rate of PT was 0.7% (56 of 8075). No transmission occurred among 2651 infants born to women who were receiving ART before conception, continued ART throughout the pregnancy, and delivered with a plasma VL <50 copies/mL (upper 95% confidence interval [CI], 0.1%). VL and timing of ART initiation were independently associated with PT in logistic regression. Regardless of VL, the PT rate increased from 0.2% (6 of 3505) for women starting ART before conception to 0.4% (3 of 709), 0.9% (24 of 2810), and 2.2% (23 of 1051) for those starting during the first, second, or third trimester (P < .001). Regardless of when ART was initiated, the PT rate was higher for women with VLs of 50-400 copies/mL near delivery than for those with <50 copies/mL (adjusted odds ratio, 4.0; 95% CI, 1.9-8.2).

Conclusions: Perinatal HIV-1 transmission is virtually zero in mothers who start ART before conception and maintain suppression of plasma VL.

Abstract access 

Editor’s notes: The risk of HIV transmission from mother-to-child is around 15-45% in the absence of maternal antiretroviral therapy (ART). This study illustrates that the risk of mother-to-child transmission is virtually eliminated when ART is started prior to conception and plasma viral load (VL) is undetectable at delivery. These findings provide further evidence supporting the implementation of Option B+ (lifelong ART as early as possible in all HIV-positive pregnant women regardless of CD4 count and VL) in low-income countries. In these settings, effectiveness of pre-conception ART will be dependent on retention in care so that women remain virologically suppressed for subsequent pregnancies. Robust surveillance data of pregnancy outcomes and other short-term and long-term risks of ART on the foetus, such as congenital malformations, and on the infant, such as pre-term birth, are also necessary to confirm that the benefit of pre-conception ART outweighs any harm.

  • share

Weighing up the risks and benefits of trial participation: understanding non-adherence in a PrEP trial

Participants' explanations for non-adherence in the FEM-PrEP clinical trial.

Corneli A, Perry B, McKenna K, Agot K, Ahmed K, Taylor J, Malamatsho F, Odhiambo J, Skhosana J, Van Damme L. J Acquir Immune Defic Syndr. 2015 Nov 3. [Epub ahead of print]

Background: FEM-PrEP - a clinical trial of daily, oral emtricitabine/tenofovir disoproxil fumarate for HIV prevention among women in sub-Saharan Africa - did not show a reduction in HIV acquisition because of low adherence to the study pill. We conducted a follow-up study to identify reasons for non-adherence.

Methods: Qualitative, semi-structured interviews (n=88) and quantitative, audio computer-assisted self-interviews (n=224) were conducted with former FEM-PrEP participants in Bondo, Kenya, and Pretoria, South Africa. Thematic analysis was used to analyze the qualitative data, and descriptive statistics were used to describe ACASI responses. Data are presented within the five categories of Ickovics' and Meisler's conceptual framework on adherence: 1) the individual, 2) trial characteristics and study pill regimen, 3) patient-provider relationship, 4) clinical setting, and 5) the disease.

Results: Participants' explanations for non-adherence were primarily situated within three of the framework's five categories: 1) the individual, 2) trial characteristics and study pill regimen, and 3) the disease. Concerns about the investigational nature of the drug being tested and side effects were the prominent reasons reported for non-adherence. Participants also described being discouraged from taking the study pill by members of the community, their sexual partners, and other participants, primarily because of these same concerns. Limited acceptability of the pill's attributes influenced non-adherence for some participants as did concerns about HIV-related stigma. Additionally, many participants reported that others continued in FEM-PrEP while not taking the study pill because of the trial's ancillary benefits and visit reimbursement - factors related to the clinical setting. Negative patient-provider relationships were infrequently reported as a factor that influenced non-adherence.

Conclusion: Despite substantial study staff engagement with participants and communities, concerns about the study pill and discouragement from others appeared to have influenced non-adherence considerably. Alternative study designs or procedures and enhanced community engagement paradigms may be needed in future studies.

Abstract access 

Editor’s notes: The authors of this important paper on a PrEP trial, end with a note of caution. They note that when interpreting the findings we should remember that the women in this study were taking a ‘study product’. The women were not taking a product of proven efficacy. Therefore, as the authors state, it would be wrong to assume that ‘African women cannot and will not be adherent if provided with PrEP outside of a clinical trial setting’. If they had been told that the product was efficacious, they may have behaved differently. This is important because a key message of the paper is that trial participants managed their participation so they felt comfortable in the trial. Many wanted to ensure they received benefits from their participation, including good health care, but they also wanted to manage risk. Risk associated with fears about the trial drug and risk from the disapproval of sexual partners about their participation. It is also very clear in these findings that the participants could manage the expectations of the trial team, by telling them what they wanted to hear during the trial. This suggests the limited value of ‘adherence questionnaires’ in some settings. The authors provide a powerful illustration of the value of mixed methods in trials of this sort. Drug concentration data told the researchers that many women were not adhering to the drug. Qualitative semi-structured interviews using this drug concentration data with the individual women helped the team to understand why. The authors also discuss the influence of community and family members in undermining participant faith in the trial. They explain the lengths that the trial team went to, to inform community members about the trial. Considerable time was given to sharing information. Doubts remained; concerns that were enough to discourage participation. This too is an important finding underlining the value of investing in community engagement in research. But it also highlights the need to find ways to enhance not just engagement, but also understanding and trust. 

Kenya, South Africa
  • share

Can nevirapine-exposed children switch to efavirenz?

Efavirenz-based antiretroviral therapy among nevirapine-exposed HIV-infected children in South Africa: a randomized clinical trial.

Coovadia A, Abrams EJ, Strehlau R, Shiau S, Pinillos F, Martens L, Patel F, Hunt G, Tsai WY, Kuhn L. JAMA. 2015 Nov 3;314(17):1808-17. doi: 10.1001/jama.2015.13631.

Importance: Advantages of using efavirenz as part of treatment for children infected with human immunodeficiency virus (HIV) include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir-boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission.

Objective: To evaluate whether nevirapine-exposed children achieving initial viral suppression with ritonavir-boosted lopinavir-based therapy can transition to efavirenz-based therapy without risk of viral failure.

Design, setting, and participants: Randomized, open-label noninferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, from June 2010 to December 2013, enrolling 300 HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission who were aged 3 years or older and had plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir-based therapy; 298 were randomized and 292 (98%) were followed up to 48 weeks after randomization.

Interventions: Participants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148).

Main outcomes and measures: Risk difference between groups in (1) viral rebound (ie, ≥1 HIV RNA measurement of >50 copies/mL) and (2) viral failure (ie, confirmed HIV RNA >1000 copies/mL) with a noninferiority bound of -0.10. Immunologic and clinical responses were secondary end points.

Results: The Kaplan-Meier probability of viral rebound by 48 weeks was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n = 4) in the efavirenz group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to infinity) and for viral failure was -0.007 (1-sided 95% CI, -0.036 to infinity). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group.

Conclusions and relevance: Among HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission and with initial viral suppression with ritonavir-boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these.

Abstract Full-text [free] access

Editor’s notes: For infants and young children (aged under three years), World Health Organization recommends ritonavir-boosted lopinavir therapy as the first-line antiretroviral therapy regimen. This is because of concerns about the increased risk of virologic failure with non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens among infants previously exposed to NNRTIs for prevention of mother-to-child HIV transmission, and better virologic efficacy of a lopinavir-based regimen even in unexposed HIV-positive infants and young children. However, there are several significant issues associated with use of boosted lopinavir therapy in children. Firstly, the syrup form of the drug has an unpleasant taste posing major adherence challenges. Secondly, there are pharmacokinetic constraints restricting its use in children who are also being treated for tuberculosis. Thirdly, there are metabolic toxicities associated with the use of boosted lopinavir therapy.

In this open-labelled non-inferiority trial, the investigators examined whether efavirenz can be used in children aged over three years, previously exposed to nevirapine as part of prevention of mother-to-child HIV transmission, who have achieved virologic suppression with lopinavir-based therapy. Efavirenz was found to be non-inferior for both the trial endpoints, namely risk of viral rebound and risk of virologic failure. There were no differences in CD4 counts or other clinical endpoints such as height- or weight-for age, anaemia or neutropenia, skin reactions or serious elevations in transaminases between the groups. In addition, children randomised to switch to efavirenz had a significantly better lipid profile than people who continued to take lopinavir-based therapy. Children randomised to receive efavirenz had significantly higher rates of neuropsychiatric disturbances, but these did not persist beyond eight weeks and notably there were no differences in proportions with behavioural problems between the two arms at the end of follow-up.

The findings of this study strongly support the switch to efavirenz in children who have achieved virologic suppression. Some caveats of this study are that the findings cannot be generalised to children who are aged under three years or to children failing boosted lopinavir therapy. In addition, it is not clear how long children can be maintained on lopinavir-based therapy before a switch to efavirenz can be made.

There is currently no guidance on managing children aged over three years taking lopinavir therapy. This study provides strong evidence to support the switch to efavirenz among virally-suppressed children aged over three years. This is important given the considerable advantages of efavirenz, including preservation of protease inhibitor-based regimens for second line treatment, harmonising paediatric with adult guidelines that recommend efavirenz as first-line therapy, once-daily dosing, better palatability and lower cost.

South Africa
  • share