Study results provide critical new data to guide HIV prevention
and treatment efforts for women and girls
Official press release, see PBS article below following this Release from IAS
posted on 7/18/2016 11:56:00 AM
Monday, 18 July 2016
CAPRISA Studies Shed New Light on Why Young Women in South Africa Have High HIV Rates
Additional Research Shows Promising Results for New Prevention and Treatment Options but Underscore Significant Challenges with Treatment Acceptance and Adherence
Durban, South Africa - Multiple studies discussed today in an official press briefing at the 21st International AIDS Conference (AIDS 2016) in Durban collectively provide new insights that will help shape future HIV prevention and treatment efforts for women and girls. Three studies by the Centre for the AIDS Programme of Research in South Africa (CAPRISA) provide new evidence on the factors that contribute to high rates of HIV infection in young women in South Africa. A new analysis of the landmark ASPIRE vaginal ring study reveals high levels of HIV protection among women who consistently used the intervention. A series of studies from the PROMISE trials provides encouraging data on options for preventing mother-to-child HIV transmission during extended breastfeeding, but also raises concerns about treatment adherence and acceptance among HIV-positive women who had recently given birth. And another study shows high efficacy and safety of a simplified, fixed-dose combination regimen for treatment-naïve women.
"These new insights pave the way to develop new prevention and treatment approaches that will protect the health of women, girls, and newborns," said Chris Beyrer, AIDS 2016 International Chair and President of the International AIDS Society. "With women accounting for the majority of adults living with HIV in sub-Saharan Africa, and new infections among young women double that of young men in the region, it has never been more critical to address this vital issue."
Commenting specifically on the CAPRISA studies discussed in today's press briefing, Salim S. Abdool Karim, Director of CAPRISA, said: "Reducing new HIV infections in young women is one of the greatest challenges in Africa. Based on our results, implementing targeted prevention interventions to break the cycle of HIV transmission while effectively treating bacterial vaginosis could reverse the devastating impact of the HIV epidemic in young people in Africa."
Research featured in the briefing included:
Age-disparate sex and specific vaginal bacteria increase HIV risk among young women in South Africa: Three CAPRISA-led studies sought to explain why young women in South Africa have high rates of HIV. One of the studies analysed the genetic HIV code from 1,589 HIV-positive people to better understand the persistent spread of HIV in a rural and an urban community in South Africa. It revealed a cycle of HIV transmission driven by high rates of new HIV infections in adolescent girls and young women from men, who were on average eight years older. Many of these men were also partners of similarly aged women, among whom HIV prevalence exceeds 60 percent.
Two additional studies investigated the role of vaginal bacteria in HIV risk. One examined the vaginal bacteria of 120 women, and found that those with an overgrowth of Prevotella bivia had an almost 20 times higher chance of acquiring HIV than those with low levels or absence of this vaginal bacterium. The other study analysed 3,334 genital bacterial proteins from 688 women, which showed that three out of five women who had "healthy" (lactobacillus-dominant) vaginal bacteria benefitted from tenofovir gel pre-exposure prophylaxis; the other women did not. Follow-up laboratory studies showed that the vaginal bacteria Gardenerella vaginalis, which predominates in the vagina when lactobacillus is not dominant, absorbs tenofovir thereby reducing its availability in the genital tract to prevent HIV infection.
[All CAPRISA data are currently under journal review; no abstracts are available.]
⋅ Session: New Evidence: Why Do Young Women in Africa Have High Rates of HIV Infection? (Session Room 1; Tuesday 19 July, 14:30 - 15:30)
- Who is infecting who? Community-wide phylogenetic transmission networks reveal young women's high HIV exposure from older men with low ART coverage
- Role of vaginal microbiota in genital inflammation and enhancing HIV acquisition in women
- Uncovering the role of the vaginal microbiome in undermining PrEP efficacy in women
Higher adherence to dapivirine vaginal ring associated with greater protection: Results of the ASPIRE study presented earlier this year at CROI indicated that a dapivirine vaginal ring decreased HIV risk by only 27 percent overall, and that efficacy differed significantly by age. The new analysis, including only those women who used the vaginal ring as directed (n=2,359), was discussed today by Jared Baeten, co-author of the study and Vice Chair of Global Health at the University of Washington School of Public Health. It showed that the ring reduced HIV risk by 65 percent, and point estimates suggested protection regardless of age (72% risk reduction for women >21 [95% CI 21-90] and 50 percent risk reduction for women ≤21 [95% CI 78-86]). These promising new findings add to the growing body of research underscoring the importance of adherence to biomedical prevention tools and give new hope to the continued development of the vaginal ring as a potential prevention option. [Summary based on submitted abstract; updated data may be presented on site.]
⋅ Abstract: Residual Dapivirine Ring Levels Indicate Higher Adherence to Vaginal Ring is Associated with HIV-1 Protection
⋅ Session: PrEP: New Drugs, New Questions (Session Room 11; Tuesday 19 July, 11:00 - 12:30 SAST)
Maternal triple antiretrovirals and infant prohylaxis both safe/effective methods for reducing mother-to-child transmission during breastfeeding: The first trial to directly compare the efficacy and safety of maternal triple antiretrovirals (mART) and infant nevirapine (iNVP) prophylaxis as strategies to reduce infant morbidity and mortality during extended breastfeeding found that both strategies were associated with very low transmission rates and high infant survival rates. HIV-infected women with CD4+ counts >350 cells/mm3 (or > country-specific threshold for therapy if higher) and their HIV-uninfected newborns were randomized at 6-14 days postpartum to mART or iNVP. These regimens were continued until 18 months post-delivery, unless breastfeeding was stopped, the infant became HIV-infected, or because of toxicity. Mother-infant pairs (n=2,431) were enrolled between June 2011 and October 2014. Median duration of breastfeeding was 15 months and not significantly different by study arm (p=0.85). K-M estimates of mother-to-child transmission of HIV at ages 6, 9, and 12 months were 0.3 percent (95% CI 0.1-0.6), 0.5 percent (95% CI 0.2-0.8), and 0.6 percent (95% CI 0.4-1.1), respectively, and not significantly different between the two arms. Infant 12-month survival rate was extremely high (98.9%) and not significantly different by regimen. Incidence rates of maternal/infant safety outcomes also did not differ significantly by regimen. Study results show that iNVP throughout breastfeeding is a safe and effective option for HIV-positive mothers who do not adhere to or tolerate ART.
⋅ Abstract: Comparing Maternal Triple Antiretrovirals (mART) and Infant Nevirapine (iNVP) Prophylaxis for the Prevention of Mother-to-Child Transmission (MTCT) of HIV during Breastfeeding (BF)
⋅ Session: Treat Early and Stay Suppressed (Session Room 12; Thursday 21 July, 11:00 - 12:30 SAST)
Treatment challenges among HIV+ women after giving birth: Results from two analyses of the largest randomized trial to date (PROMISE) evaluating postpartum antiretroviral therapy for women with high CD4 counts (≥400 cells/mm3) demonstrated an urgent need to increase treatment acceptance and adherence. Judith Currier from the David Geffen School of Medicine discussed results of the PROMISE 1077HS study among women from 52 sites in Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand, and the United States (n=1,652). Women were randomized to continue or discontinue ART. Among the women selected to continue treatment (n=827), nearly one-quarter (23%) had virologic failure. Among a subset of these women who had been tested for drug resistance (n=155), 86 percent did not have resistance to their current regimen, indicating non- adherence led to virologic failure. A second study (IMPAACT PROMISE), presented by Lynda Stranix-Chibanda of the University of Zimbabwe shared concerning results regarding acceptance of treatment. Among 1,483 HIV-positive women who had recently given birth, about one third (34%) declined to go on treatment, even after being counselled about the benefits of starting treatment regardless of CD4 count. Both studies demonstrate the significant challenges that will need to be addressed to successfully implement WHO's recommended "treat all" approach. [Summary based on submitted abstract; updated data may be presented on site.]
⋅ Abstracts: Randomized Trial of Stopping or Continuing ART among Post-partum women with Pre-ART CD4 > 400 cells/mm3 (PROMISE 1077HS) & Low acceptance of early antiretroviral therapy (ART) among post-partum women enrolled in IMPAACT PROMISE Studies across the globe
⋅ Session: Treat Early and Stay Suppressed (Session Room 12; Thursday 21 July, 11:00 - 12:30 SAST)
New simplified treatment option for HIV+ women: Phase III results from an international, randomized, open-label study (ARIA) among treatment-naïve adult women (n=495) show promising results of a simplified treatment regimen after 48 weeks. Catherine Orrell of the Desmond Tutu HIV Centre presented the trial results, which found that a once-daily fixed dose combination of dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) had superior efficacy and a favourable safety profile compared to a regimen of ritonavir boosted atazanavir plus tenofovir disoproxil fumarate/emtricitabine (ATV+RTV+TDF/FTC). Among women taking the fixed dose combination, 82 percent were virally suppressed (HIV-1 RNA <50 c/mL) compared to 71 percent taking the other regimen (adjusted difference 10.5%, 95% CI: 3.1% to 17.8%, p=0.005). The safety profile of the fixed dose combination treatment was also favourable compared to the other regimen, with fewer drug-related adverse events reported in the DTG/ABC/3TC group. These results provide important information to help guide treatment decisions for women. [Summary based on submitted abstract; updated data may be presented on site.]
⋅ Abstract: Superior Efficacy of Dolutegravir/Abacavir/Lamivudine (DTG/ABC/3TC) Fixed Dose Combination (FDC) compared with Ritonavir (RTV) Boosted Atazanavir (ATV) plus Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC) in Treatment-Naïve Women with HIV-1 Infection (ARIA Study)
⋅ Session: Treatment Evolution: New Drugs, New Reality (Session Room 6; Thursday 21 July, 16:30 - 18:00 SAST)
How vaginal bacteria could be stoking HIV cases and blocking prevention
BY Heather Boerner July 18, 2016
CAPE TOWN, South Africa - Jacqualine Ncube is doing everything she can to be among the 40 percent of South African women who remain HIV-negative into middle age.
At 19, she's already participated in an HIV vaccine trial. She comes to the Desmond Tutu HIV Foundation Youth Centre here in Cape Town every two months to be tested for HIV. She even takes a combination antiretroviral pill every night at 9 p.m. that prevents her from acquiring HIV if she's exposed. And when it comes to sex, she insists that her boyfriend use a condom. No method is 100 percent protective, she said, so she covers all her bases.
When asked if her boyfriend ever scoffs at condoms, Ncube cracked a wry smile and shook her head emphatically.
"He'd never tell me something like that, because he knows what the answer is that he's going to get," she said. "I'm so rude when it comes to someone telling me what to do. I don't want to be told what to do. I want to be my own person."
By some estimates, about 40 percent of HIV infections are associated with biological mechanisms - mechanisms that scientists are just beginning to unravel.
She also wants, she said, "to be protected, always."
But for a young woman to be protected always in this part of sub-Saharan Africa is a tall order. In some parts of the country, women her age have an 80 percent chance of acquiring HIV in their lifetimes. Not only are the social and economic odds against her, but a fluke of biology may be against her, too. By some estimates, about 40 percent of HIV infections are associated with biological mechanisms - mechanisms that scientists are just beginning to unravel.
Some of that unraveling is being done in real time. At the International AIDS Conference in Durban today, researchers at the Center for the AIDS Programme of Research in South Africa (CAPRISA) will unveil startling new evidence of a bacterial culprit that could be responsible for as many as two out of every five new cases of HIV among women. They'll also reveal how another bacteria blocks the effectiveness of those pills Ncube takes.
At the heart of these discoveries is an area of research that was once considered a biological dead zone: the vaginal microbiome. Scientists have known since the 19th century that the vagina is colonized by bacteria. But it wasn't until the 1990s that researchers began to discover the lush diversity of life there - and how that diversity may contribute to women's risk for HIV. It's no coincidence, it turns out, that women who live in areas with high rates of HIV also have disproportionately high rates of a microbiome imbalance called bacterial vaginosis (BV). The inflammation caused by BV, and the specific bacteria that make up that imbalance, can increase women's susceptibility to the virus. With the research presented today, the field - and women's chances of staying HIV-negative - could take another leap forward.
A Natural, Robust Defense
When Dr. Richard Cone, professor of biophysics at Johns Hopkins University, was in medical school in the 1950s and 60s, the general attitude toward the vagina was, well, disinterested. In 1882, Albert Doderlein had identified Lactobacillus in the vagina, a friendly microbe that is also present in things like yogurt. And that, Cone said, was that.
"All the work we've done in the last 20 years could have been done 100 years ago," Cone said. "But there was just no interest."
By the late 1980s and early 1990s, Cone was interested, though. And so were microbiologists like Sharon Hillier, who began her career working in reproductive health, as well as other microbiologists around the world who began to see this as a fertile field of study. Cone, Hillier, and others began submitting grant applications to the National Institutes of Health (NIH). Then, in the 1990s, a leadership change at the agency expanded funding.
Quickly, it became clear that there's more to the vaginal microbiome than Lactobacillus. Indeed, there's a world in there. A 2005 study in the New England Journal of Medicine identified more than 100 different types of bacteria in the vagina.
What researchers began to realize was that several strains of Lactobacillus had the power to protect women from sexually transmitted infections (STIs), including HIV - and that others left women even more exposed.
First, the good news. The microbiome has a secret weapon against HIV: lactic acid. But the conditions have to be just right.
Here's how it works. First, Lactobacillus has to dominate the vaginal microbiome. Second, the pH in the vagina has to drop below 4 - a low pH that conforms, perhaps not coincidentally, with a healthy pH in the gut (stomach pH tends to hover around 3.5).
That's the pH of a dill pickle.
If you have a Lactobacilli-dominated microbiome, you've already created a hostile environment for invading bacteria, viruses and even sperm, all of which thrive at a higher pH. But when you combine Lactobacilli-produced lactic acid with a very low pH, the environment isn't just hostile. The lactic acid becomes deadly to invading bugs, Cone said.
At a very low pH, lactic acid turns into, in Cone's words, "a small oily molecule" capable of slipping through the membranes of invading cells and releasing acid directly into the bug.
Boom - dead virus.
"The point at which Lacobacillus begins to secrete enough lactic acid to load up the mucosa with protons is at about 3.8," said Cone. "It gets charged and forms a layer that is truly protective."
And though the protective effect is modest, it still adds a layer between women and bugs.
"I like to say," Cone said with a laugh, "that women need protection from sperm and germs."
Living in Ncube's World
The problem is that Lactobacillus doesn't dominate the microbiomes of many of the world's women - especially women most at risk for HIV. A 2010 study of American women in the Proceedings of the National Academy of Sciences found that Lactobacillus dominated the microbiomes of Asian and white women, but accounted for only 59.6 and 61.9 percent of the microbiomes of Latina and Black women, respectively. The same has been found in sub-Saharan Africa.
That diversity in the microbiome, and the associated higher pH and increased inflammation is part of what we call BV.
Saying someone has BV is as specific as saying that someone has a cold. Yes, BV is associated with specific symptoms, such as watery discharge and malodor. But only specific combinations of bacteria are associated with those symptoms. So it's possible to have asymptomatic BV - that is, diversity in the microbiome that increases pH but doesn't cause discharge or odor. And it's possible to have those symptoms and be so used to them that they don't strike you as abnormal, or cause you to visit a doctor for treatment.
"Women don't come in," said David Fredricks, member of the Vaccine and Infectious Disease Division of the Fred Hutchinson Cancer Research Center and author of that 2005 NEJM article, "and say, 'My pH is off.' They say, 'I have malodor' or 'I have discharge.'"
But that's exactly what's happening, especially in women at high risk for HIV. In the U.S., the overall BV rate hovers around 29 percent. But for African American women, whose rates of HIV are 20 times higher than their white counterparts, BV rates can be as high as 51 percent. In Ncube's Cape Town, where four in 10 new HIV infections occur among women 15 to 24, rates of BV reach 47 percent. And more than two-thirds of those women report no symptoms, said Shaun Barnabas, a PhD candidate studying the vaginal microbiome in Cape Town.
Finding the Smoking Gun
And it turns out that none of the bacteria associated with the symptoms of BV are the ones associated with HIV risk. For that, you have to turn to one strain: Prevotella bivia.
At least that's the finding of a study released today at the International AIDS Conference. The study, based on the sequencing and analysis of the microbiomes of 120 South African women, found that it was only women with P. bivia in their microbiome who also were statistically more likely to have HIV, too-by a lot.
"What we found," said CAPRISA's Karim, "was that if a woman had ever had Prevotella, she had an almost 20-fold higher risk for inflammation and HIV acquisition than other women."
Of the 120 women studied, 10 percent had ever had Prevotella. But that 10 percent accounted for 41 percent of all infections. That means that two out of five women in the study had acquired HIV because P. bivia set the stage.
It does that, Karim said, by producing proteins known to marshal a strong immune response. That signal causes immune cells called CD4 T cells to flood to the vaginal surface. Unfortunately, those cells are exactly the ones HIV targets to infiltrate and co-opt. Unrecognized by the rest of the immune system, those infected cells are transported to the lymph nodes. And voila - swift, efficient HIV infection.
That means that two out of five women in the study had acquired HIV because P. bivia set the stage.
And while the results are based on a small sample of patients and need to be replicated in other parts of the continent and world, the findings are already drawing praise from high places. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease at the NIH, called it "quite an important observation."
"Being able to identify a specific villain is good," he said. "Will manipulating the microbiome be the major thing that ends AIDS? No. But is it one of many, many things that need to be pursued, to help us possibly understand the novel ways we can prevent HIV in women? Absolutely."
HIV Prevention At Stake
But that's not all Karim's team discovered. They also unveiled data today that linked another bacterial strain - Gardnerella vaginalis - to lower effectiveness of the HIV prevention pill Truvada in women.
Karim's team started the study because they had noticed, in HIV prevention trials, that the efficacy rates were all over the place in women. A recent study out of University of North Carolina that predicted that, for women to receive full protection from the HIV prevention pill Truvada, they couldn't miss even one dose. Gay men, meanwhile, had been shown in other studies to benefit from the full power of Truvada with just four doses a week.
"We need to figure this out," Karim said he thought.
So they pulled the frozen microbiome samples from women who'd participated in CAPRISA's study of an HIV prevention gel made from one of Truvada's components, tenofovir, and started sequencing the microbiome. Pretty soon, a clear picture emerged. Women with Lactobacillus-dominated microbiomes showed "quite a reasonable effectiveness from tenofovir," he said. "But in women without Lactobacillus-dominated microbiomes, tenofovir had almost no benefit."
"Gardnerella was just gobbling up the tenofovir. It was taking it inside the cell, so it wasn't available to protect against HIV."
So what gives? To find out, they took cultures of Lactobacillus and the other bacterial strains prevalent in the women's microbiomes and they exposed them to tenofovir. With Lactobacillus? There was almost no effect. The Lactobacillus just sat there, and so did the tenofovir. They coexisted happily. With Gardnerella? Within four hours, half of the tenofovir disappeared. Within 24 hours, almost all of it was gone.
"I was just floored," said Karim. "Gardnerella was just gobbling up the tenofovir. It was taking it inside the cell, so it wasn't available to protect against HIV."
Whether this finding genuinely answers the question of why women have to be so perfectly adherent to Truvada to achieve the same protection as gay men will require further study. CAPRISA's results were based on tests done in a lab-the real proof will come when researchers treat for Gardnerella and watch how that changes the effectiveness of Truvada in women. Just such a study, on periodic treatment of BV and its affect on other STIs, is underway in Kenya.
Jared Baeten, vice chair of global health at the University of Washington and one of the investigators of the PARTNERS PrEP prevention trial and demonstration project, said that their studies have shown that Truvada has virtually eliminated HIV acquisition in women in their studies. So Gardnerella may not impact the protection women get from oral PrEP.
"I think the results will probably be most relevant to local application of tenofovir in gel form," he said. "[CAPRISA's] results are very important for thinking about which medicines to use as microbicides"-that is, topical prevention medicines, like the tenofovir gel.
Still, the results could change how policy makers scale up HIV prevention. In the middle of explaining these results last week, Karim interrupted the conversation to take a call from Dr. Margaret Chan, director-general at the World Health Organization.
A Healthier Future
The good news is that diagnosing and treating BV is simple and inexpensive, even without diagnosing and treating specific strains. You can buy a pH testing kit at a pharmacy and, if the pH is above 4.5, Karim said, you can get a prescription for metronidazole (Flagyl) and treat it yourself. Getting Lactobacillus into one's microbiome is a little trickier, though researchers are trying to devise a variety of solutions to that problem now.
All this may mean, for Ncube and other women like her, that there's another tool they can use to keep themselves safe, forever, from HIV. When she spoke to PBS NewsHour, Ncube didn't know about Karim's results, and it was unclear if she'd ever been tested or treated for BV. For now, Ncube will keep doing what she can do to protect herself. And when she looks ahead, she said cheerfully, she will keep going, keep protecting herself. She's willing, for instance, to keep taking the pills as long as it takes for the epidemic to change.
"Forever," she said, "Yeah, I'm willing to take it as long as it [HIV] lasts."