What is new in HIV/AIDS research in developing countries?
Corresponding Author Anatoli Kamali, Uganda Virus Research Institute, P.O. Box 49, Entebbe, Uganda. E-mail: email@example.com
HIV epidemic has had greatest impact in sub-Saharan Africa (SSA) and mainly in East and Southern Africa with HIV prevalence in some parts going up to 30%. In the recent years, considerable HIV research on prevention, treatment and care, and vaccine has been conducted in many developing countries and provided evidence-based knowledge to control the epidemic. However, there have also been disappointing results in HIV prevention trials such as in HIV vaccine and microbicide trials. Despite these outcomes, important lessons have been learnt that help in designing future trials. This article examines the recent advances in HIV research in developing countries. The most recent HIV prevention research has demonstrated the effect of male circumcision on HIV acquisition, and lack of impact of HSV-2 treatment on HIV transmission and acquisition. Use of HIV antiretroviral drugs (ARVs) for HIV prevention is a new area that has attracted interest and a number of trials are examining the effect of oral Pre-Exposure Prophylaxis on HIV acquisition and also looking at the potential of ARVs in reducing infectiousness. Progress has been made in HIV treatment, monitoring treatment efficacy and toxicity as well as evaluation of different models of ART delivery. HIV vaccine research has, however, faced most challenges despite many efforts that have been put in. Looking into the future, there are ongoing trials that will hopefully generate important information to strengthen HIV policies in the next few years. There are, however, many other gaps in HIV research that need to be urgently addressed.
Quoi de neuf dans la recherche sur le VIH/SIDA? Revue
De nouvelles technologies de prévention du VIH sont développées et évaluées à l’aide d’essais contrôlés randomisés (ECR), y compris la circoncision masculine (CM), le traitement des IST, les microbicides, la prophylaxie pré-exposition (PrEP), la suppression du HSV-2 et le vaccin contre le VIH. Cependant, seuls 4 des 36 ECR majeurs à ce jour ont montré une efficacité contre la transmission du VIH, dont 3 étaient sur la CM montrant environ 60% de protection chez les hommes hétérosexuels, mais un essai récent ne rapporte aucune protection pour les partenaires féminines des hommes circoncis infectés par le VIH.
Les résultats d’une Phase III de gel vaginal microbicide PRO2000, prévus pour Novembre 2009, sont attendus avec impatience surtout qu’un plus petit essai (HPT035) a montré une réduction non significative de 30% dans l’incidence du VIH. Les microbicides à venir comprennent des antirétroviraux, mais leur efficacité reste encore à déterminer.
Plusieurs essais d’efficacité de PrEP et deux sur des vaccins contre le VIH sont également en cours. La recherche d’un vaccin VIH a rencontré des défis uniques et les quelques essais achevés n’ont pas montré d’efficacité. Les personnes infectées ne déclenchent pas de réponse immunitaire contre le virus à cause du temps très court qu’il requiert pour se cacher dans les cellules hôtes. Ceci est associéà sa capacité de muter et à détruire les cellules clés du système immunitaire.
Différents schémas de traitement du VIH et des modèles ont montré des résultats encourageants. Les résultats les plus récents indiquent que le traitement antirétroviral (ART) peut être administré en toute sécurité et efficacement dans les pays à ressources limitées et que les services de laboratoire réguliers offrent peu de bénéfices cliniques par rapport à la surveillance clinique attentive par des agents de santé formés et supervisés. Des questions majeures demeurent sur le moment de changer d’ART et le moment de débuter le traitement. Il y a également un intérêt croissant sur la possibilité d’utiliser des antirétroviraux pour prévenir la transmission du VIH.
Que hay de nuevo en la investigación del VIH/SIDA? Revisión
Se están desarrollando nuevas tecnologías para la prevención del VIH que están siendo evaluadas mediante ensayos controlados y aleatorizados (ECA), incluyendo la circuncisión masculina (CM), el tratamiento de enfermedades de transmisión sexual (ETS), microbicidas, la profilaxis pre-exposición (PrPE), la supresión del VHS-2 y la vacuna para el VIH. Sin embargo, a día de hoy, solo 4 de 36 ECAs han mostrado eficacia sobre la transmisión del VIH, 3 de los cuales eran en CM y mostraron una protección aproximada del 60% en hombres heterosexuales. Sin embargo, en un ensayo reciente se ha reportado la no protección para las parejas femeninas de los hombres circuncidados infectados con VIH. Los resultados del ensayo de fase III con el gel vaginal microbicida PRO2000, son esperados con ansias para Noviembre 2009, ya que un ensayo más pequeño (HPT035) mostró una reducción no significativa del 30% en la incidencia del VIH. Los microbicidas futuros incluyen antirretrovirales, pero su eficacia aún está por determinar.Varios ensayos pre-exposición y dos ensayos de eficacia de vacunas de VIH también están en camino. La investigación en vacunas de VIH tiene retos únicos, y los pocos ensayos que han terminado no han mostrado eficacia. Los individuos infectados no presentan una respuesta inmune frente al virus debido a que el periodo transcurrido antes de que el virus se esconda de las células hospederas es corto. Este hecho está asociado a la habilidad que tiene el virus para mutar y destruir células claves del sistema inmune. Diferentes modelos y regimenes de tratamiento para el VIH han mostrado resultados esperanzadores. Los resultados más recientes indican que la terapia antirretroviral (TAR) podría entregarse de forma segura y efectiva en lugares con recursos limitados, y que los servicios regulares de laboratorio ofrecen pocos beneficios clínicos, comparados con una monitorización clínica cuidadosa realizada por trabajadores sanitarios bien entrenados y monitorizados. Las preguntas más relevantes continúan siendo cuando cambiar el TAR y cuando comenzar el tratamiento. También hay un interés creciente sobre la posibilidad de utilizar antirretrovirales para prevenir la transmisión del VIH.
Currently, World Health Organization estimates that there are approximately 33.4 million people living with HIV/AIDS worldwide (UNAIDS 2009). The HIV epidemic has had its greatest impact in sub-Saharan Africa and mainly in East and Southern Africa with HIV prevalence in some parts going up to 30%. This study discusses three main areas of recent HIV research on HIV prevention, treatment and care, and HIV vaccine with emphasis to research in sub-Saharan Africa. However, this study does not discuss advances in paediatric HIV research. Many research institutions in Africa have contributed to advances in medical research, including that on HIV/AIDS. This has been possible through strong partnerships between researchers and institutions in Africa with those in the North, but also through South–South collaboration, and secondly, through funding agencies that have specifically targeted promoting research in African institutions, such as the European Developing Countries Trials Partnership (EDCTP).
Despite many efforts to date to control the HIV epidemic through what we know works, such as abstinence–behaviour change–condom (ABC strategy), treatment of sexually transmitted diseases, and HIV testing and counselling, a high global HIV prevalence prevails (UNAIDS 2009). Encouragingly, HIV treatment has become more available even in developing countries in recent years (WHO/UNAIDS 2005). However, HIV has continued to spread faster than treatment, and it is estimated that for every two patients who start antiretroviral treatment (ART), 5–6 new infections occur. The gap between new infections and those starting ART is likely to widen, as there is growing evidence that treatment initiatives will not cope in many developing countries and that many new patients will not be able to be started on treatment. HIV prevention thus remains a key issue in HIV/AIDS research.
Several HIV prevention strategies have been evaluated worldwide, many of these in developing countries. Broadly, these can be categorised into two: behavioural change interventions and biomedical interventions. To date, over 30 major randomized controlled trials have been conducted, and disappointingly, only four of these have shown efficacy against HIV transmission. The first was the Mwanza syndromic treatment of sexually transmitted infections that showed 40% reduction (Grosskurth et al. 1995). The other three were the recent male circumcision trials that showed approximately 60% protection among heterosexual circumcised men (Auvert et al. 2005; Bailey et al. 2007; Gray et al. 2007). These data have shown that male circumcision is probably the most effective biomedical HIV intervention to date. A comparable trial among circumcised HIV-infected men has, however, recently reported that there is no protection for female partners (Wawer et al. 2009). After these results, WHO/UNAIDS made several important recommendations that male circumcision offers partial protection and should be used as part of a comprehensive HIV prevention package and that circumcision needs to be conducted safely, with appropriate counselling and after-care. While overwhelming evidence of efficacy has been established, there is need for further research on how to scale up the intervention in real life.
Building on extensive epidemiological evidence of interaction between Herpes Simplex type 2 (HSV-2) and HIV infection, a few trials have recently been completed evaluating impact of HSV-2 treatment on HIV transmission. One study in Mwanza, Tanzania, examined whether HSV-2 suppressive therapy with acyclovir 400 mg twice per day reduces HIV incidence in HIV-negative women (Watson-Jones et al. 2008). There was no overall effect of acyclovir on the incidence of HIV (rate ratio for the acyclovir group, 1.08; 95% CI 0.64–1.83). The second trial was a phase III trial of HSV-2 treatment to prevent HIV transmission in discordant couples, which was carried out in 7 African countries and following 3408 couples in which the partner with HIV and HSV-2 used oral acyclovir twice a day (Celum et al. 2010). Acyclovir treatment reduced the frequency of genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20–0.36; P < 0.001) and HIV levels in the blood by 0.25 log10 copies per millilitre (95% CI, 0.22–0.29; P < 0.001), but these effects did not translate into reduction in the risk of HIV transmission (HR with acyclovir, 0.92, 95% CI 0.60–1.41; P = 0.69). Another phase III trial examined whether HSV-2 suppression with acyclovir reduced the risk of HIV-1 acquisition among HIV-negative, HSV-2 positive women in Africa and men who have sex with men (MSM) in Peru and the USA (Celum et al. 2008). Similarly, there was no reduction in HIV acquisition with an incidence of 3.9 in the acyclovir group and 3.3 per 100 person-years in the placebo group [hazard ratio 1.16 (95% CI 0.83–1.62)].
What is the role of HIV antiretroviral drugs in HIV prevention? There is evidence that prophylaxis has been successful, especially with other infectious diseases such as malaria, tuberculosis, and Pneumocystis pneumonia. For over a decade, ARVs in combination regimens have been used in HIV management with excellent outcomes in both developing and developed countries. ARVs have also been used successfully in prevention of mother-to-child transmission (MTCT) (Guay et al. 1999; Shaffer et al. 1999; Wiktor et al. 1999) and post-exposure prophylaxis (PEP) (Smith et al. 2005). Most of the new ARVs now in use have shown good safety profiles as well as good drug levels in the genital tract and long intracellular half-lives, which could potentially favour their use in prevention of sexually transmitted HIV infection. There has also been good efficacy in animal models using ARVs to prevent simian immunodeficiency virus (SIV) or HIV infection (Tsai et al. 1995; Subbarao et al. 2006). These encouraging developments have led to a postulation that ARVs could potentially prevent HIV through oral Pre-Exposure Prophylaxis (PrEP) (Youle & Wainberg 2003; Smith 2004).
Several PrEP studies are ongoing and investigating the safety and efficacy of either daily tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC)/TDF for PrEP in various populations. Two of these are efficacy trials that have recently been launched in Africa in 2009. The first is FEM-PrEP, a phase III trial among high-risk women in five African countries, and results were expected in 2012. The second is MTN 003/VOICE, a phase IIB trial in five African countries. Some of the ongoing trials are expected to report results in 2010–2011 (phase II/III among IDUs in Thailand; iPrEx trial among MSM in several countries). If any of these ongoing trials show efficacy, it will be important to consider adherence to a daily regimen among healthy uninfected individuals at risk of HIV in real-world settings. It is also important to evaluate the feasibility and potential efficacy of other alternative PrEP dosing, such as intermittent regimens. Only two pilot studies, supported by the International AIDS Vaccine Initiative (IAVI), are evaluating the safety, acceptability, and adherence to daily and intermittent PrEP regimens of FTC/TDF among at-risk populations in Kenya and Uganda, and the results are expected in late 2010. In the event that these two pilot trials show favourable results for intermittent dosing, large-scale trials will need to be designed in at-risk populations.
Besides evaluating use of ARVs in PrEP, there is a new area of HIV prevention now being considered for the use of ARVs among HIV-infected individuals (Castilla et al. 2005; Baggaley et al. 2006). This new thinking is based on the evidence that ARVs reduce viral load in both blood and genital secretions (Vernazza et al. 1997; Zhang et al. 1998), and thus potentially reducing infectiousness (Pinkerton 2008). One clinical trial testing this hypothesis is a phase III trial among 1750 serodiscordant couples in several countries to determine whether reducing the viral load in the HIV-infected partner (by providing ART) could prevent HIV transmission to the uninfected partner (HPTN 052). This debate has now been extended to a suggestion that universal HIV testing and treatment (test and treat strategy) of those found to be positive could eliminate HIV infection by 2050 (Granich et al. 2009). However, this suggestion is based on mathematical modelling, and neither how such an intervention could be scaled up nor its efficacy in a real life setting is known. Appropriate evaluation of its feasibility and acceptability at population level is needed in the first instance.
Another HIV prevention strategy that has attracted international interest and funding is the use of vaginal microbicides. Much of this scientific agenda has been driven by the fact that over 80% of current HIV transmissions are through heterosexual intercourse, with women being more vulnerable owing to transmission dynamics, socio-economic factors, and limited control over safer sexual practices (McCormack et al. 2001). There is therefore an urgent need for female-controlled HIV prevention methods especially in the developing world. Although this is a potential HIV prevention strategy, there have been several disappointing results of effectiveness trials with early generation products such as nonoxynol-9, SAVVY, cellulose sulphate, and Carraguard (Cates & Feldblum 2008). More recently, PRO2000 vaginal gel, which had reduced HIV infection by 30% in a phase IIb trial – approaching statistical significance (P = 0.1) (Karim et al. 2009) – proved ineffective in a larger phase III trial of the Microbicide Development Programme (MDP301) (Chisembele et al. 2010).
Despite these disappointing results with the early generation products, valuable information has been generated on which to build future microbicide research. There is now evidence from the recent trials that adherence to gel use among the female participants is generally high, and the products are liked by both men and women, reporting that the gel increases sexual pleasure (Ramjee et al. 2001; Bentley et al. 2004; Bakobaki et al. 2005). The next-generation microbicide products are ARV-containing products that have evidence of efficacy against HIV in vitro (Klasse et al. 2008). The most advanced ARV in the pipeline is Tenofovir (an NRTI), which is now available in a gel formulation that can be applied inside the vagina with an applicator. Two trials are currently assessing the effectiveness of intravaginal use of Tenofovir in preventing HIV. CAPRISA 004 is a phase IIb trial in South Africa testing Tenofovir 1% gel when used before and after sex, results of which are expected in mid 2010. The second is the MTN 003 (VOICE) trial conducted in Uganda, Zambia, Zimbabwe, South Africa, and Malawi, a phase IIb testing the safety and effectiveness of Tenofovir gel, Tenofovir tablets, and Truvada tablets for prevention of HIV infection in 4200 women. There are several other ARV-containing microbicide products in the development pipeline, and some already show promising safety profiles to use as vaginal gel in HIV prevention. These include UC-781, dapivirine (NNRTIs) in phase I/II, and Maraviroc (CCR5 blocker) in the preclinical phase.
Whereas all microbicide products tested to date have been formulated in gel form, there are now efforts towards formulating some ARV-containing microbicides in a vaginal ring. The International Partnership for Microbicides (IPM) is currently conducting safety and acceptability trials of Dapivirine vaginal ring and gel in East and South African countries. One major advantage of a vaginal ring would be that it would allow slow release of an active microbicide over a period of several weeks or longer, hence overcoming the need to insert gel daily or at every sex act. IPM is also doing some preclinical studies on a formulation of ring and gel that combines Dapivirine and Maraviroc. This combination strategy, if proved viable, would offer some advantages over single ARV combining microbicide such increased efficacy, although it could also lead to increased toxicity. Such factors will need to be evaluated in early clinical trials. In addition to vaginal rings, other potentially more user-friendly formulations are being explored, such as film tablets and capsules. These formulations are, however, in very early stages, and data on safety and acceptability will be essential prior to moving onto clinical trials.
Treatment for HIV and related opportunistic infections (OIs) has probably been one of the most successful areas in HIV epidemic. The use of highly antiretroviral therapy has improved the survival and quality of life of HIV-infected individuals. Equally important are the benefits of prophylactic treatment of OIs in HIV infected either alone (pre-ART) or in combination with ART, for example using cotrimoxazole (Zachariah et al. 2007). Progress has also been made on how best to monitor disease progression among those on treatment and evaluation of different models of ART delivery especially in resource-poor countries. The following is a summary of the most recent studies that have helped address these areas.
Prophylactic treatment of opportunistic infections
Although ART reduces the burden of OIs after restoration of the immune system, there is still a role of prophylaxis of OIs especially in settings where only a small proportion of ART-eligible patients are able to access treatment. An example is cryptococcal meningitis, which remains one of the major OIs among HIV-infected patients with a very high mortality rate especially in sub-Saharan Africa. This is likely to remain so among those individuals, who, for various reasons, are not able to start ART despite reaching CD4 level treatment threshold. A recent study evaluated primary prevention of cryptococcal meningitis using 200 mg fluconazole prophylaxis three times per week among HIV-infected Ugandan adults with CD4 < 200 cells/μl (Parkes-Ratanshi et al. 2009). Fluconazole was found effective in preventing cryptococcal meningitis both before starting ART and post-ART initiation.
Monitoring ARV treatment
As roll out of ART increases in many parts of Africa, monitoring HIV treatment efficacy and toxicity events could face many challenges and data are required on which are the most cost effective monitoring strategies. The recently completed DART multicentre trial in Uganda and Zimbabwe evaluated clinically driven monitoring (CDM) vs. laboratory plus clinical monitoring (LCM) among adult ART-naïve HIV patients with CD4 < 200 cells/μl who were initiated on triple ART (DART Trial Team 2010). Overall, the trial demonstrated that ART could safely be provided without laboratory monitoring. There was no difference in mortality and disease progression in the first 2 years of treatment. The trial results suggested that thereafter CD4 cell count monitoring could only be useful for guiding on when to switch to second line treatment from the third year onwards.
Evaluation of other ART delivery models
One of the limiting factors in ART adherence is the cost and time loss incurred by travelling to the health care facilities for those who live far away, especially in rural Africa where means of transport are not adequate. In addition, high HIV prevalence settings are likely to have an inadequate health care infrastructure and staffing to be able to cope with the huge number of patients who require ART initiation and close monitoring. This has necessitated examining the feasibility and the impact of decentralized models of ART delivery, such as home-based delivery using trained lay field workers. The home-based model is believed to be easier for patients and has been shown to have positive social outcomes (Apondi et al. 2007). It could also help in easing congestion at the already busy health facilities in many developing countries. One cluster-randomized trial in southeast Uganda that assessed whether home-based HIV care was as effective as facility-based provided probably the most evidence-based data. The trial showed that home-based care delivery using trained lay workers was as effective as facility-based ART in terms of mortality, virological response, and CD4 count. The overall costs of service provision were reported to be similar for both models, although the cost of accessing care was considerably cheaper for patients in the home-based model (Jaffar et al. 2009).
HIV vaccine research
Development of an HIV vaccine is the greatest scientific priority and best hope to end the HIV epidemic. The long-term goals for an AIDS vaccine would be to primarily prevent acquisition of HIV infection and secondly to control HIV infection if the infection occur. HIV vaccine research has faced the most challenges in HIV research despite the many efforts governments, international agencies, industry, advocates, and research groups have put in HIV vaccine discovery. There are many factors that have attributed to these challenges: the ability of HIV to infect and destroy the key cells of the immune system in a relatively short time combined with its overall genetic diversity makes vaccine development very complex. Unlike other viral infections that are able to elicit neutralizing antibodies after primary infection, this is not very clear in HIV infection. The HIV-neutralizing antibodies documented to date have not shown any effect in controlling HIV infection. There is, however, now an increasing interest in this area following the isolation of broadly neutralizing antibodies (bNAbs), including PG6 and PG16 recently isolated in an African patient by a consortium led by the IAVI (Walker et al. 2009). Prior to the identification of these two antibodies, there had been four more bNAbs (b12, 2G12, 2F5, and 4E10) identified, but they had been difficult to use in HIV vaccine development. Another challenge in HIV vaccine development has been difficulty in generating critical data on immunological responses from animal models, as much of this has been based on SIV rather than HIV. To date, there have been a few HIV vaccine efficacy trials conducted, and all have shown no efficacy on HIV, and in one of them, there was an indication of an increased risk (Buchbinder et al. 2008). The most recent phase III vaccine trial was the Thai trial (RV144) that tested a prime boost combination of ALVACR HIV and AIDSVAXR. The trial demonstrated that the vaccine regimen was safe and of borderline significance in preventing HIV infection (Rerks-Ngarm et al. 2009).
Despite several prevention efforts, the HIV epidemic continues unabated especially in developing countries. There are a few countries, such as Uganda and Senegal, that were able to bring down HIV infection rates in the 1990s. This was largely through reduction in risky sexual behaviour. Unfortunately, there are now indications that the rates are no longer falling in Uganda (Shafer et al. 2008); there is recent evidence indicating a levelling off of infection rates that may in fact be rising in certain age groups. These worrying developments require redoubling prevention efforts using available evidence-based tools. There is also an urgent need to develop policies where there is sufficient scientific evidence on HIV prevention, for example developing national policies on circumcision. It is now over 3 years ago that HIV prevention through circumcision was demonstrated through three well-conducted clinical trials. But many countries where this relatively simple technique, when incorporated in the existing comprehensive prevention package, could avert many HIV infections are still developing such a policy, and scaling up has not happened. It is crucial that the interaction between researchers, governments, international agencies, and advocacy groups is strengthened to help in moving policy formulation processes faster.
HIV prevention clinical trials have had some disappointing results in the past decade. But this should not cause despair. There are many lessons learnt from these past trials that help in developing more promising new prevention techniques and designing future trials. Some of the planned clinical trials with new products will be large-scale, multicentre studies that will require large funding, which few funding agencies can afford to support on their own. One mechanism to overcome this will be, for example, through a number agencies coming together to support one large clinical trial. However, such mechanisms for multi-donor funding need to be developed and where they exist, strengthened. Additional funding is also required for continued support to the research infrastructure and training in many developing countries to enable the conduct of clinical trials.
Although there have been many advances in HIV research, we need to recognize that there are many gaps that need to be addressed. These include understanding the HIV epidemiology and transmission dynamics among neglected populations such as fishing populations, men who have sex with men, and commercial sex workers. Despite great progress in HIV treatment, there are also gaps that need to be addressed. When to start ART, when to switch, and what to switch to are some of the important questions. There is also still a big research gap on how best to deliver HIV treatment and sustain care in resource poor settings.
In the coming few years, the scientific community, policy makers, and international agencies look forward to the forthcoming results of the ongoing PrEP and the phase IIb tenofovir microbicide trials. The outcome of these trials will influence future HIV prevention strategies using ARVs but are also likely to generate new concerns and raise more research questions. One concern is whether PrEP may lead to more risky sexual behaviour owing to a feeling that those on PrEP may be protected. Some possible research questions this approach could raise are the following. What will be the impact on treatment access for the ART eligible HIV patients? Will PrEP increase level of toxicity and resistance if the approach goes to scale and how would these be measured? Whatever new efficacious HIV techniques become available, they will need to be additional to the existing prevention tools and not substitutes of them.