Perspective: Conducting HIV Prevention Research in South Africa
Challenges of and successes in conducting HIV research in KwaZulu-Natal, the epicenter of the South African HIV epidemic
By Koleka Mlisana, Francois van Loggerenberg, and Salim Karim*
Sub-Saharan Africa is the most severely HIV-affected region of the world and accounts for 63% of global infections(1). The HIV epidemic in South Africa is characterized by very high prevalence rates, linked to persistently high incidence rates. In 2006, HIV prevalence in pregnant women was 29% nationally, and 39% in KwaZulu-Natal, the worst-affected province. Hence both prevention and treatment are a high priority in this setting.
However, working in these areas also presents significant challenges, including resource constraints and bottlenecks. As additional HIV prevention trials get underway, identification of hurdles and bottlenecks not only in the design, but also in the implementation of running such trials, will be of paramount importance.
South Africa is well positioned to conduct HIV prevention trials, with an established clinical research infrastructure, world-class laboratories, and trained clinical trialists. Recently South Africa was hosting a Phase IIb test-of-concept trial known as HVTN 503, or Phambili, with Merck’s AIDS vaccine candidate (MRKAd5). But in September of 2007, immunizations and enrollment were stopped because data from the HVTN 502 companion study—known as the STEP trial—testing the same vaccine candidate showed it was ineffective.
As the field prepares for other Phase IIb test-of-concept and Phase III efficacy trials with vaccines and microbicides, the limitations of conducting research in highly-affected areas need to be taken into consideration. South Africa, which has one of the highest HIV prevalence and incidence rates in the world, yet better resources than most developing countries, is in an advantageous position to shed light on some of these challenges.
State of the epidemic
In South Africa, about 5.5 million people–approximately 19% of the adult population–are currently estimated to be living with HIV(2). The epidemic has grown explosively. Between 1990-2005, national HIV seroprevalence among antenatal clinic attendees increased from 0.7% to 29.1%(2-4). The province of KwaZulu-Natal is at the most advanced stage of the epidemic and here antenatal HIV prevalence reached 39% last year.
The majority of HIV infections in this region occur through heterosexual transmission and about two to three times more young women are HIV infected, as compared to young men(1). In one rural KwaZulu-Natal district, the HIV prevalence reached almost 50% in 2006 among 20- to 29-year-old women.
Not only are young women in South Africa more severely affected but they also acquire their infections at a much earlier age than men(5). These striking gender differences have contributed to the rapid growth of the country’s HIV epidemic, along with high rates of sexually-transmitted infections (STIs)(6), the migrant labor system(7), and high rates of gender-based violence(8). Although not unique to South Africa, marginalization and discrimination on the basis of race and/or ethnicity has also played a role in influencing vulnerability to HIV infection(9).
Challenges of establishing a cohort
Between August 2004 and May 2005, the Centre for the AIDS Programme of Research in South Africa (CAPRISA) established a cohort of HIV-uninfected high-risk women for an acute HIV infection study (CAPRISA 002) that aimed to describe immunological, virological, and clinical characteristics of HIV-1 subtype C acute infection in Durban(10), and to determine the incidence in a high-risk population. Risk factors such as sex work, STIs, and HIV prevalence have been used in the past(11) as the basis for selecting populations for HIV prevention studies because it is assumed that these populations would also have high HIV incidence rates. However, these measures are crude and unreliable and at best only hint that there might be high incidence in a highly generalized epidemic such as the one in this region.
The aim of this study was to recruit female sex workers (FSWs). Although women are often reluctant to identify themselves as FSWs, 79% of our cohort consisted of self-identified FSWs when evaluated during behavioral risk assessments.
Establishing HIV-negative cohorts in such high prevalence areas can be a great challenge. In many areas, routine HIV testing is not yet common. Offering HIV testing in preparation for research studies may lead many individuals to undergo HIV testing who otherwise would not have had easy access to this service. Therefore many HIV-infected individuals are often uncovered in the process of trying to identify uninfected trial volunteers. In this sex-worker cohort, the overall HIV prevalence at screening was nearly 60% (95% CI; 55.9% - 62.8%). The HIV prevalence varied dramatically over time from 83% in the first month of screening to 17% in the last month (Figure 1). This variation indicates how unpredictable the enrollment process can be.
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The implications of high prevalence
There are many complications associated with conducting HIV prevention studies in severely affected regions. First, the higher-than-anticipated prevalence can have an indirect impact on clinic staff. They can easily become overwhelmed by having to counsel and follow up such large numbers of HIV-positive patients, who most often are not expecting the diagnosis. It is critical that employees at the clinic, especially counselors, are given an opportunity to be debriefed on the stress associated with this kind of work. Counseling may need to be provided to staff members who become disillusioned by the number of HIV-infected patients they are seeing in their clinics.
Such high prevalence rates can also put pressure on recruitment deadlines and screening numbers in prevention research, and can increase the patient burden at local clinics identified as referral partners for the treatment and management of HIV infection. It is therefore critical to provide support to these clinics in the form of training, access to medicines, resources, and counseling and support staff, if necessary, to assist them in dealing with a significantly expanded workload. It is also important that memoranda of agreement regarding referrals and the sharing of critical resources are in place prior to screening efforts, and that resources to support and expand existing facilities are part of large grants from the outset.
It is also essential to develop strategies when working with marginalized populations such as FSWs, which are difficult to access. It is often useful to identify networks of peer sex-workers to assist in establishing and maintaining cohorts. Visits to sites often need to be arranged outside regular work hours, at times and places that are convenient for the research participants.
Communication with these volunteers is often challenging because of high mobility and a lack of fixed residential addresses or contact numbers. Mobile telephones, which are widely used in South Africa, have therefore proven to be an extremely useful communication tool. A web-based short message service (SMS) has been used to send pre-approved mobile phone text messages to willing participants and proved to be an effective tool for clinic visit reminders. This is a cost-effective service and also provides a convenient electronic and paper audit trail. Almost all participants either had their own cell phone, or had a friend who had a cell phone. Mobile telephone contact and SMS messaging were used in the HVTN 503 trial to call trial participants to the clinic to notify them of the trial suspension, and subsequently, to inform them when immunizations were halted.
High mobility and low socioeconomic status of many research participants in this environment can further complicate cohort retention. Fortunately, retention rates for CAPRISA 002 were over 84% after two years, with only 5% of the HIV-negative cohort falling out of contact during the follow-up period. This retention is reassuring for future microbicide and vaccine studies, which could have even greater retention rates in light of the perceived benefits of the intervention to the participants. This retention success underscores the value of having a dedicated network of peer workers and of making a concerted effort to engage the community in the research. Making use of all available contact channels, especially the use of mobile phones, is essential for maintaining follow-up.
In addition to communication and retention, there are other unexpected challenges when working with highly-affected populations. One of these is the high prevalence of domestic violence. An alarming one-third (32.4%) of the women in the CAPRISA 002 cohort either reported or had clinical evidence of abuse and in 70% of cases, the abuser was an intimate sexual partner. Responding to this challenge required establishing relations with available support structures like the Network on Violence Against Women and necessitated specific training for research staff, especially counselors, on domestic violence.
Measuring incidence
HIV incidence measures are essential for monitoring the future trends of the epidemic, for understanding the dynamics of the epidemic, for designing HIV prevention trials, and for estimating the number of new infections—all of which are essential for planning and monitoring interventions. Accurate measurements of incidence are crucial in the face of prevention trials, as HIV seroconversion is critical in endpoint-driven vaccine trials. Statistical power of these trials is dependent on accurate estimates of the incidence rate. Longitudinal cohorts are therefore often the best for incidence measurement, but can be very expensive and time consuming. In the CAPRISA 002 study cohort, the high HIV prevalence was coupled with a remarkably high HIV incidence rate. With 4,784 monthly visits by 245 participants, 28 acute HIV infections were identified for an annual seroincidence rate of 7.2 per 100 person-years (95% CI; 4.5-9.8), despite intense risk-reduction counseling for all participants.
It is important to note for prevention trials testing microbicides or AIDS vaccines that high risk sexual behavior continues despite the best attempts by study staff to provide condoms and risk-reduction counseling. HIV prevention studies will therefore need to ensure that there are comprehensive plans for risk-reduction counseling, especially since HIV infection is often the endpoint for these studies and the community may believe researchers are therefore not motivated to reduce infection rates. It can be confusing for communities to reconcile the research goals of identifying HIV infection, with the need to engage in intensive risk-reduction counseling. The focus on prevention needs to be very clear to avoid confusion. Communities also need to be sensitized to the fact that, no matter how intensive risk-reduction counseling is, some individuals will remain at risk for HIV infection.
Comprehensive risk-reduction counseling needs to include an assessment of individual risk and a personalized risk-reduction plan, in conjunction with providing technical (condom use), social (safer sex communication and communication with partners), and interpersonal problem-solving skills(12). Counselors need to be trained adequately in the provision of this counseling and ensure that its impact is sustained throughout the trial. Improved rates of condom use were observed in CAPRISA cohorts within the first six months of enrollment, but they were often not sustained beyond nine months or a year. Strategies to sustain behavioral changes are therefore greatly needed.
It is also clear that many of these risk-reduction efforts may be even more difficult to implement in the lives of the women we recruit. This is reinforced by data on STIs and pregnancy from the CAPRISA 002 study. Overall, 29% and 19% of women were infected with an STI at baseline and at the first six-month visit respectively, in spite of condom provision and monthly risk-reduction counseling. While none of the women were pregnant at enrollment, there were 32 pregnancies [incidence of 8.5 per 100 person-years (95% CI; 5.6-11.5)] in the cohort. One-third of these pregnancies resulted in early terminations, suggesting a high rate of unplanned or unwanted pregnancy. Pregnancy is one of the key challenges in HIV prevention trials and is one of the main reasons women discontinue participation in a trial(12). It is becoming necessary to consider requiring hormonal contraception as an inclusion criteria in prevention trials to prevent pregnancy because of inconsistent and unreliable condom use by participants.
Tied to the provision of risk-reduction counseling is the need to provide prompt diagnosis and treatment of STIs—especially those linked to HIV acquisition and transmission. The identification of these infections is also essential for understanding their impact on infection rates in prevention trials.
Male circumcision has been shown to be up to 60% protective for men in terms of HIV acquisition(13-15), leading the World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) to recommend that male circumcision be promoted as part of an effective HIV prevention program. Opinions presented at the 2007 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Sydney, Australia, indicated that circumcision can also reduce the incidence of other reproductive health problems, such as urinary tract infections in male infants, and penile cancer, chancroid, and human papillomavirus (HPV) in adult men(16). There is some indication that female partners of circumcised men may also benefit, with lower rates of cervical cancer and Chlamydia(16). Although there have been strong calls from the WHO and many delegates at the recent South African AIDS conference in Durban, the South African National Health Department has not made clear declarations around universal access to circumcision in South Africa. We believe that prevention studies conducted here in the future will need to ensure that men have access to this relatively inexpensive, proven intervention for reducing the risk of HIV infection. However, this needs to be part of a comprehensive HIV prevention strategy that includes counseling and testing, treatment of STIs, as well as the provision of male and female condoms.
Future challenges
One of the other challenges of conducting HIV prevention research is the lengthy ethical review process. All documentation for HIV prevention trials must be reviewed by local ethics committees or Institutional Review Boards (IRBs). South Africa is fortunate to have high quality IRBs attached to the local universities, which provide excellent review capacity and turn-around times. Vaccine trials require further approval from the Institutional Bio-safety Committees (IBCs), and capacity in this regard may require further development. In places where IBCs do not exist, they will need to be set up prior to the review of vaccine trial protocols.
Although the expertise of the regulatory bodies to review Phase I and II clinical trials has been developed to a limited extent, further improvement is necessary. Before more Phase IIb test-of-concept trials begin, regulatory bodies need to be prepared for these reviews. Efficacy trials involve new challenges and raise questions about the standard of care available within the general population and offering trial participants the best care available.
Prevention trials also face another challenge of co-enrollment of participants who do not disclose their participation in other prevention trials. In some South African populations, unemployment is very high and participants can take advantage of the monetary reimbursement they receive for time and transportation during a clinical trial. This obviously can have a negative impact with regard to safety of the participants, as well as the validity of data collected in these studies. In addressing this issue, researchers might need to share participant information to exclude co-enrollment, which in turn has confidentiality and other ethical implications. Systems will need to be set up to address this issue. There has been very little, and only anecdotal, evidence of this at CAPRISA trial sites. Researchers are currently working with other investigators at prevention trial sites in and around Durban to avoid this problem in the future.
Lack of infrastructure and human resources is another one of the major obstacles to conducting HIV prevention research in developing countries. Investment into developing human expertise is critical in these settings if we are to meet the laboratory demands of vaccine and microbicide research. Attaining and maintaining trained and qualified laboratory staff on processing peripheral blood mononuclear cells (PBMCs) caused a major delay in all five South African vaccine trial sites for the HVTN 503 (Phambili) trial. And now that immunizations have been stopped, retaining these trained laboratory workers has become another challenge.
It is very difficult in South Africa to attract and retain well-trained and experienced staff in contractual research posts. Undergraduate programs that expose students to research and post-doctoral scholarship funding mechanisms need to be established. Clear career paths for junior researchers must also be designed to ensure retention of staff. Once trained, staff mobility between sites causes frequent disruption and delays in trials.
Notwithstanding the differences and study objectives in the various international research networks, uniformity and standardization of some of the laboratory assays is also essential for the already overstretched laboratories to run smoothly. Quality control and assurance systems need to maintain stringent standards to ensure quality immunogenicity data from these sites. Immunogenicity assays are currently confined to one or two laboratories in South Africa and when additional Phase IIb and III prevention trials get underway, it will be essential to expand this expertise.
The disappointing results of the STEP study, which led to the premature closure of the Phambili trial, have left the South African HIV vaccine trial investigators with many new challenges, including the key question of how to maintain clinical trial sites. This will impact recently established sites—and those that were solely involved in that trial—the most. The concern about job security among trial staff members must also be addressed. But amidst all these challenges, it is crucial to continue the search for additional, effective HIV prevention strategies.
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*Dr. Koleka Mlisana is a medical microbiologist and Director of the Acute Infection Project at CAPRISA; Francois van Loggerenberg is a registered research psychologist and Coordinator of the Acute Infection Project; and Dr. Salim Karim is a clinical infectious diseases epidemiologist and Director of CAPRISA.
References
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