6.7 Salim Abdool Karim — Stopping the Spread of HIV in Developing Countries

Salim Abdool Karim: [00:00:00] Good afternoon, everyone. I'm very sorry that I'm not able to be there with you in person due to personal circumstances but I hope that this video will give you a sense of my comments around stopping the spread of HIV in developing countries. I'd like to thank the organizers for inviting me [00:00:30] to address this issue and I think it's important for us to reflect on the history of the HIV epidemic as we think of its future.

If we look at the global HIV epidemic, in 2015, there were close on to 37 million people living with HIV. (1) 1.1 million deaths occurred and importantly, 2.1 million new HIV infections. [00:01:00] This translates into 5,700 new HIV infections each day, but if we look at it in the global context, if we look at these 37 million people, we see that close on to or around 33 million of that 37 million live in developing countries, mostly in Africa. If we eliminate [00:01:30] those parts of the world that are predominantly in the developed world, we eliminate roughly in the region of about four to five million individuals. That still leaves us with the bulk of the HIV epidemic occurring in developing countries.

If we look at the top 10 countries where people are living with HIV, we see that these 10 countries account for just over [00:02:00] half of all of the HIV infections in the world. The three top countries South Africa, India, and Kenya, between them, account for around three-tenths of all the HIV infections, giving you some sense of how some countries contribute a disproportionate burden to the overall global HIV epidemic. Looking at South Africa on its own, [00:02:30] a country with less than 1% of the world's population, South Africa has between 18% and 19% of the world's HIV infections.

How did all this occur? How is it that South Africa has such a high burden of HIV? What's the history of HIV in this country? Well, we've been through the five stages [00:03:00] of the HIV epidemic in South Africa. It started off where we saw the first cases predominantly in men who have sex with men, in hemophiliacs, and in those high-risk populations. What we saw was predominantly subtype B infections.

But it wasn't until the late 1980s, early 1990s that we saw the introduction of the virus into the [00:03:30] general population, the general heterosexual population. During that period, we saw the initiation of the generalized HIV epidemic. It wasn't until 1994 when South Africa had just moved from the apartheid state into a democracy that we really saw the period of rapid growth of the HIV epidemic, at a point where [00:04:00] the number of infections was doubling almost every year.

But as mortality caught up with the high incidence rate, we began to see this leveling off towards the plateau. It's during that plateau period, that AIDS deaths were at their highest and we refer to that as the AIDS mortality phase or the death period, of the HIV epidemic in this country. [00:04:30] Following the departure of President [Thabo] Mbeki (in 2008), we saw the introduction of antiretrovirals to scale, and now we are beginning to just start seeing the ART impact phase, where we are hoping to see the number of new infections slowly going down and the number of existing infections going up due to survival.

It's in the context of this history of this HIV [00:05:00] epidemic, we see that South Africa is not homogenous, that indeed different parts of the country have different prevalence rates with the eastern corridor having the highest prevalences of HIV, and that is in the province of KwaZulu-Natal. Looking at the way in which the HIV epidemic was growing, it was very clear to us that we needed to build the capacity to respond [00:05:30] to it. We needed to have research capabilities. The first of those initiatives that I was involved in was in 1996 when we applied to the Wellcome Trust to create the Africa Centre [for Health and Population Studies]. The grant, which we secured from the Wellcome Trust in 1997 created one of South Africa's first HIV research centers in South Africa.

I'm going to talk [00:06:00] principally about building capacity in KwaZulu-Natal the epicenter of the HIV epidemic in South Africa. Indeed, while we were doing this, our colleagues in Johannesburg, in Cape Town, similarly, were also creating this capacity. Shortly after the Africa Centre had been created, I was at that time at the MRC, and secured two grants from the NIH to create a vaccine, [00:06:30] HIV prevention trials unit, and an HIV vaccine trials unit. That was the post-HIVNET period when the first of the networks were created for prevention and vaccine separately.

Then shortly thereafter, in response to the NIH call under the CIPRA banner, we applied to create CAPRISA at the University of KwaZulu-Natal, Nelson Mandela Medical School in partnership with [00:07:00] four other institutions. Both the MRC unit and CAPRISA were both created on the basis of funding that we had secured from the NIH. The NIH played a key role in building the early capacity in South Africa to address the HIV epidemic. In 2003, the Doris Duke Medical Research Institute opened here [00:07:30] at the Nelson Mandela Medical School. Then a few years later, it expanded into the K-RITH (Kwazulu-Natal Research Institute for Tuberculosis and HIV), funded by the Howard Hughes [Medical Institute]. That's the institute where today the Africa Centre, CAPRISA, and K-RITH are located.

In 2003, I led an initiative funded by the South African government to create a biotechnology institute. This institute was really about looking at funding mechanisms to support [00:08:00] and build new biotechnology. That successful grant led the basis for a whole range of initiatives, not just in HIV but also in TB, a focus on diagnostics and treatment. It was in a whole range of different areas. Then finally, working with colleagues in the US, Bruce Walker and Bill Jacobs, in particular, we secured funding from the Howard Hughes Medical Institute to create K-RITH, [00:08:30] a new initiative to look at the interaction between tuberculosis and HIV, which is one of the centerpieces of the health challenge that we face right here in South Africa.

In building that capacity, we were really thinking about what were the challenges we were facing, and how did we need to respond, and what capacity did we need to have in place to respond appropriately? [00:09:00] As the HIV prevalence is going up, the thing that became obvious to us seeing patients in the wards was the rapid increase in the number of tuberculosis patients. In fact, we went from a situation where when I did ward rounds, TB patients were predominantly old and male. In a very short space of time, they quickly became female and young. [00:09:30] That shift highlighted for us the importance of this interaction between TB and HIV. We had been able to see that just in terms of mortality, and we were already seeing that HIV and TB between them were contributing just over a third of all the deaths in South Africa, and so we needed to be able to address this issue.

Colleagues from Yale [00:10:00] Gerry Friedland and Bruce Walker and a range of us, sitting around the table, trying to think about how to deal with this challenge. We realized that we really did not have sufficient evidence on what's the best approach to treat patients with TB and HIV. Indeed on the one hand, the conventional wisdom was to delay the initiation of ART because of all of the challenges we see. We see as soon as you initiate ART in patients who are on TB [00:10:30] treatment, you'd have to deal with the drug interactions, the drug toxicities, you have to deal with the immune reconstitution. There are all of these complications that encouraged clinicians to hold antiretroviral therapy until the patient was well and stable following the initiation of TBs treatment. Often because of the drug interactions, antiretrovirals would only be started at the end of TB treatment. [00:11:00] 

To address that issue, we initiated a trial, and it was funded as part of the original creation of CAPRISA funded by the NIH was to do a study, to look at what is the most appropriate way to treat patients with HIV and TB, and at what's the appropriate timing of the initiation of antiretrovirals. This study showed that we could achieve a 56% lower mortality [00:11:30] simply by integrating antiretrovirals with TB treatment in patients who are co-infected. (2) These results led to a rapid advice released from the WHO, where the findings of our child were included in the rapid advice. They became the basis of country level guidelines, including the US government's DHHS.

Certainly within South Africa, we saw [00:12:00] a very rapid uptake of these results. In fact, shortly after we had the results, we had meetings with treasury, with the office of the president. He wanted to announce it on World AIDS Day in 2009. President [Jacob] Zuma announced that all patients with both TB and HIV will get the antiretrovirals if their CD4 count is 350 or less at a time when we were treating only patients with CD4 counts below 200—but importantly made the point that TB [00:12:30] and HIV will now be treated under one roof. He was making it very clear that we were now going to integrate both therapies and the implementation of these findings would lead and could lead to about 10,000 deaths being averted in South Africa alone.

Indeed, the whole push to initiate antiretrovirals early has come from several other studies. [00:13:00] We've seen how globally, we've seen an increase in ART coverage, to the point where in 2015 they were 17 million people on antiretroviral therapy as part of the overall goal to try and achieve 90-90-90. If we look at just the way in which ART scale-up was achieved, we went from just about 2 million [00:13:30] people being on antiretroviral treatment in 2005 to almost 17 million people in 2015. In 10 years, 15 million people were put onto treatment. But even at 17 million people on ART coverage globally of antiretrovirals is below 50%. In others there is much more that still needs to be done.

If we [00:14:00] focus for a moment on the global strategy UNAIDS and through the last world health assembly adopted an overall strategy. One of the key pieces of that strategy to deal with the global HIV epidemic is the 90-90-90 strategy. Indeed many countries across the globe and many developing countries have already adopted this approach, which aims to achieve 73% viral suppression [00:14:30] amongst all those who have HIV infection.

But despite all of the scale up of treatment, despite all of these efforts to scale up circumcision, condom use, we are lagging seriously in HIV prevention. If you look at the last three years of the global HIV epidemic, we have seen consistently in the region of 1.9 [00:15:00] to 2.1 million new infections each year over the last three years. That must be viewed against the backdrop that we have set a target of half a million new infections by the year 2020. We are a long way away from our target. We have a lot more still in store.

We've known that HIV has [00:15:30] dramatically high HIV prevalence rates—we see are in young women. If you look at just within our own rural community here in KwaZulu-Natal, the prevalence of HIV ranges from 11.5% in 16-year-old pregnant women, all the way to over 50% among those who are 25 and over. (3) Just for a moment, imagine the burden that that means in this community, [00:16:00] the seven antenatal clinics that serve this community, a woman walking in 25 years or older has more than—Is more likely to be HIV positive than not. It's dealing with this HIV situation in young women that presents us with this big challenge, and this is not something new. This is something we have known for the last 26 years.

One of the first community-based HIV [00:16:30] surveys undertaken in Africa was actually undertaken by Quarraisha [Abdool Karim] back in 1990. (4) We had just come back from Columbia University, had been working with Zena Stein while we were at the school of public health. One of the issues she kept hammering us on was: You've got to got to understand what is going on in the HIV epidemiology. You need to understand who is most affected, why and so when we came back, we said, "Well, let's start trying to address that [00:17:00] issue."

We created the study in northern KwaZulu-Natal in the community, and this picture emerged. This picture that showed us if you follow the red line in the age group 15 to 19 young women are already close to the peak of the HIV prevalence compared to teenage boys who have almost no HIV infection. It's this age differential, that these young girls are sleeping with older men [00:17:30] on average, about eight to 10 years older, that is the main driving force in this epidemic. We described this back in 1990, so that's 27 years ago. And if we look at a sub-district level, if we look at the prevalence of HIV in young women, we see as you go up the Southern and Eastern corridor of Africa, we see that the bulk of [00:18:00] the high prevalence areas are occurring where young women have high prevalence rates. You see that quite clearly in this diagram.

Why is it? Why are we seeing this? Well, we already know from the work we did in 1990, that there's this age disparity, but we never been able to quantify it. We've never been able to understand how this is driving the overall high burden of disease. We began to understand that [00:18:30] when we did a study in just over 10,000 people in this rural and urban community in the KwaZulu-Natal Midlands and where we sequenced well over a one-and-a-half thousand viruses and we tried to look at all of the clusters. (5) If we looked at the clusters, the thing that was most striking for us was the large number of clusters that we saw, which had a woman in her 30s, a woman in a teen years, [00:19:00] and a man in the 30s. That showed us that if you look at the overall direction of the way in which HIV is spreading, you see the cycle of HIV transmission. That men in their 30s have just acquired HIV infection from women in their 30s. They don't know that they have HIV infection. They're not on treatment and they have high viral loads. And they are having a liaison with a young woman, a teenager or somebody, a woman in her [00:19:30] early 20s. It's those infections, those high rates of infections in these young women who are sleeping with older men, on average 8.7 years older, that as they grow older they become the woman in the group of 30-year olds, who infect the next group of men who infect the next group of young women and so you create the cycle.

This cycle has been the basis of what we've been trying to break [00:20:00] by trying to find technologies that would protect women from HIV and that the traditional strategies that we had, the ABCC's ("abstinence, behavior, condoms, circumcision"),  were not really effective in the context of focusing on and protecting that group which had the highest burden of HIV in South Africa. And so In 2003, we developed the CAPRISA 004 study (2007–2010), and there were many others working exactly in this area. Sharon Hillier, [00:20:30] there were people working in the field in FHI (Family Health International), Ron Roddy, and Paul Feldblum, there are a whole range of people. We were entering this field to try and better understand how we could contribute and what is it we could do?

Working with Gilead and developing an approach to using tenofovir gel, we decided to design a study to look at the efficacy [00:21:00] of tenofovir gel to prevent HIV and HSV-2. We pursued this despite and amidst severe criticism. In fact, Nature published an article which was entitled "Trial doomed by design, say critics," in which many of our critics came forward and said, "The design of your study, your dosing strategy, you're going to create resistance. We don't think this has good chance of working." (6) [00:21:30] There were many different opinions on the subject, but we persevered.

In 2010, we released our findings at the [18th] International AIDS Conference in Vienna. (7) This, shared with the world provided the first proof of concept that antiretrovirals could prevent sexually transmitted HIV infection. Shortly after, the World Health Organization held a [00:22:00] consultation to map out the next steps. The findings were ranked among the top 10 scientific breakthroughs in Science. Overall, this laid a good foundation that enabled this whole field to blossom. Indeed, many others were working in this area at the same time as us, were starting to the release their results shortly thereafter. The iPrEx study, the Partners PrEP study. They were coming out in quick succession [00:22:30] presenting to the world great new results about how antiretrovirals could be used for prevention.

But today as we look at the spectrum of the data we have available, they are not consistent. The data we have seen from all these different trials show that we have quite a lot of varying efficacy and much of this due to the challenges of adherence, principally in young women, the group that has the highest risk. [00:23:00] Despite all of that, we do now accept that tenofovir based pre-exposure prophylaxis is effective in preventing HIV. If we look at the evidence that the World Health Organization used, they subsequently came out with a guideline promoting PrEP for men who have sex with men, and indeed, a range of other risk groups where [00:23:30] HIV incidence is high. The overall approach is to take daily Truvada (tenofovir+FTC) as PrEP.

We've seen good progress with HIV prevention tools in the last few years as we've seen the use of antiretrovirals both for treatment and for prophylaxis. We really still need new HIV prevention technologies for women. Whether it deals with vaccination or [00:24:00] passive immunization or structural interventions, such as cash transfers. I hope you will excuse my use of Donald Trump's picture to illustrate gender-based violence. We're going to need more than just simple biotechnologies. We're going to need more than simply providing an injection. We're going to have to do this in conjunction with behavioral interventions, structural intervention so that [00:24:30] we really throw the kitchen sink at this problem, because it's not going to be solved by some magic bullet.

But we're also seeing now new approaches to circumvent the challenge of adherence in the use of antiretrovirals for prevention. We have an opportunity to choose a future for the HIV epidemic in Africa. Under the banner of UNAIDS, we've had [00:25:00] several consultations and this concept that should we be talking about the end of AIDS. Well, the end of AIDS IS a long way away. It's merely an aspirational vision. The usual epidemiological concepts of elimination, eradication don't really apply to HIV because we don't have a cure, and we don't have a vaccine. If we think about the end of AIDS, particularly end of AIDS as a public health threat, we're talking about [00:25:30] epidemic control. Can we get to a point where the incidence is much lower, and it becomes a more manageable condition. In fact, there is much that we can learn from mother to child transmission. There is a global plan to eliminate new HIV infections in women. Indeed, they've set targets, and they are not doing too badly in terms of getting to those targets. I think the next goal must be to think about epidemic control in all groups.

That's not [00:26:00] going to be easy. You've already seen that, in fact, the number of new HIV infections hasn't been going down, that we have seen between 1.9 and 2.1 million new infections steadily over the last three years. We got to do better because we have tools. We need to be using all of these tools. As Tim Hallett and his group have shown us in this mathematical modeling, that if we just [00:26:30] focus on scaling up to and going really at high coverage with the tools we have, we can have a huge impact on the HIV epidemic. (8) Yes, HIV epidemic control is achievable. However, we have to have a vaccine and/or cure before we can talk about elimination, before we can really be talking about the end of AIDS.

I'd like to conclude by just highlighting the developing countries have over [00:27:00] 80% of the global burden of HIV infection. Despite the impressive progress in treatment rollout aiming for the 90-90-90 UN AIDS goal prevention is seriously lagging behind. We need a focused effort to scale up existing prevention strategies, but also to develop new prevention strategies, particularly focusing on ways in which to break the cycle of HIV transmission. [00:27:30] There are many challenges facing developing countries trying to achieve epidemic control, but this should not deter us. We won't end AIDS tomorrow, but it has to be part of our long-term vision. Thank you very much. [00:27:49] [END OF AUDIO]

Citations

1. UNAIDS. “Global AIDS Update 2016.” UNAIDS, 2016. https://www.unaids.org/en/resources/documents/2016/Global-AIDS-update-2016.
2. Abdool Karim, Salim S., Kogieleum Naidoo, Anneke Grobler, Nesri Padayatchi, Cheryl Baxter, Andrew Gray, Tanuja Gengiah, et al. “Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy.” New England Journal of Medicine 362, no. 8 (February 25, 2010): 697–706. doi:10.1056/NEJMoa0905848.
3. Kharsany, Ayesha BM, Janet A Frohlich, Nonhlanhla Yende-Zuma, Gethwana Mahlase, Natasha Samsunder, Rachael C Dellar, May Zuma-Mkhonza, Salim S Abdool Karim, and Quarraisha Abdool Karim. “Trends in HIV Prevalence in Pregnant Women in Rural South Africa.” Journal of Acquired Immune Deficiency Syndromes 70, no. 3 (November 1, 2015): 289–95. doi:10.1097/QAI.0000000000000761.
4. Abdool Karim, Quarraisha, Salim S. Abdool Karim, Bipraj Singh, Richard Short, and Sipho Ngxongo. “Seroprevalence of HIV Infection in Rural South Africa.” AIDS 6, no. 12 (December 1992): 1535–40.
5. Oliveira, Tulio de, Ayesha B M Kharsany, Tiago Gräf, Cherie Cawood, David Khanyile, Anneke Grobler, Adrian Puren, et al. “Transmission Networks and Risk of HIV Infection in KwaZulu-Natal, South Africa: A Community-Wide Phylogenetic Study.” The Lancet HIV 4, no. 1 (January 2017): e41–50. doi:10.1016/S2352-3018(16)30186-2.
6. Check, Erika. “HIV Trial Doomed by Design, Say Critics.” Nature 448, no. 7150 (July 1, 2007): 110–11. doi:10.1038/448110a.
7. Abdool Karim, Quarraisha, Salim S. Abdool Karim, Janet A. Frohlich, Anneke C. Grobler, Cheryl Baxter, Leila E. Mansoor, Ayesha B. M. Kharsany, et al. “Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women.” Science 329, no. 5996 (September 3, 2010): 1168–74. doi:10.1126/science.1193748.
8. Cremin, Ide, Ramzi Alsallaq, Mark Dybul, Peter Piot, Geoffrey Garnett, and Timothy B. Hallett. “The New Role of Antiretrovirals in Combination HIV Prevention: A Mathematical Modelling Analysis.” AIDS 27, no. 3 (January 28, 2013): 447–58. doi:10.1097/QAD.0b013e32835ca2dd.

Index

• 6.1 Sharon Hillier — Development and Application of Pre-exposure Prophylaxis (PrEP)
• 6.3 Bruce Walker — Role of T Cells in Controlling HIV Infection
• 18th International AIDS Conference, Vienna, 2010
• Abdool Karim, Quarraisha (b. 1960)
• adherence, patient compliance
• Africa Centre for Health and Population Studies
• Africa, sub-Saharan Africa
• antiretroviral therapy (ART)
• CAPRISA (Centre for the AIDS Programme of Research in South Africa)
• circumcision
• clinical trials (phases of clinical research)
• Columbia University
• condom
• Department of Health and Human Services, US (HHS)
• Doris Duke Medical Research Institute
• epidemiology
• Family Health International (FHI, FHI 360)
• Friedland, Gerald
• FTC (emtricitabine, Emtriva, Coviracil)
• funding and grants
• Gilead
• Hallett, Timothy B.
• hemophilia
• herpesviruses
• heterosexual transmission of HIV
• HIV vaccine
• Howard Hughes Medical Institute (HHMI)
• India
• iPrEx (Iniciativa Profilaxis Pre-Exposición) study, 2007–2011
• Kenya
• KwaZulu-Natal
• Kwazulu-Natal Research Institute for Tuberculosis and HIV (2012–2016)
• Mbeki, Thabo (b. 1942)
• Medical Research Council (MRC) 
• mother-to-child transmission of HIV
• MSM (men who have sex with men)
• National Institutes of Health (NIH)
• Page:CAPRISA 004 study (2007–2010)
• pediatrics, pediatric AIDS
• pre-exposure prophylaxis (PrEP)
• Science (journal)
• South Africa
• Stein, Zena A.
• tenofovir (TDF, Viread)
• Trump, Donald (b. 1946)
• tuberculosis (TB)
• UNAIDS
• University of KwaZulu-Natal, Nelson Mandela Medical School
• viral load
• Wellcome Trust
• World AIDS Day (December 1)
• World Health Organization (WHO)
• Yale University, Yale School of Medicine
• Zuma, Jacob (b. 1942)