Global treatment plays key role in HIV prevention

As antiretroviral therapy becomes better tolerated and less costly, a growing number of domestic and international public health organizations are advocating global treatment for HIV patients regardless of CD4 count or viral load. While these recommendations are allowing patients to live longer and remain virally suppressed, there also is evidence suggesting that expanding coverage will have a significant impact on the rate of new infections.

“The HIV epidemic is, without doubt, the biggest epidemic that has exploded across the world in our lifetimes, and since it has exploded we’ve been able to come up with drugs that treat HIV and keep people alive,” Peter Godfrey-Faussett, MBBS, FRCP, professor of international health at the London School of Hygiene & Tropical Medicine and senior science adviser for the Joint United Nations Program on HIV and AIDS (UNAIDS), told Infectious Disease News. “It has also become clear that when people are on antiretroviral treatment, they become hugely less infectious. As a result, putting people on treatment has a double benefit: It keeps those people alive, but it also reduces the chance of ongoing transmission of the virus.”

Photo courtesy of Columbia University Mailman School of Public Health

This finding has led to international campaigns such as the UNAIDS’ 90-90-90 strategy, which aims to increase the number of people with HIV in care while reducing the risk for new infections. However, recent data suggest additional funding and novel interventions are needed to reach the campaign’s 2020 goal.

To explore the impact of treatment on the spread of HIV, Infectious Disease News spoke with several experts about the origins of treatment as prevention (TasP) and the challenges of enrolling and retaining patients in care.

Decades of evidence

Also referred to as global treatment, TasP is a prevention strategy that focuses on the use of ART to limit new HIV transmissions. Although currently supported by WHO, the CDC and other health organizations, the relationship between treatment and infectivity has not always been well recognized.

“We’ve known that transmission was limited in people with low viral loads — we’ve known that for nearly 20 years,” Infectious Disease News Chief Medical Editor Paul A. Volberding, MD, director of the AIDS Research Institute at the University of California, San Francisco, said in an interview. “And yet, we didn’t really connect the dots that treating the virus would prevent transmission, even though we knew that post-exposure prophylaxis worked. The real question is, ‘Why did it take us so long to get here when we really should have known?’ ”

The first evidence came in the late 1990s in conjunction with a landmark study on the prevention of vertical transmission, explained Wafaa M. El-Sadr, MD, MPH, professor of epidemiology and medicine and director of the International Center for AIDS Care and Treatment Programs at Columbia University. In the HIVNET 012 randomized trial, researchers assigned zidovudine or nevirapine to pregnant women with HIV at the onset of labor and found that the use of these drugs significantly reduced the risk for mother-to-child transmission of HIV.

“It was noted that when a pregnant woman with HIV takes antiretroviral drugs, this can prevent transmission to her infant,” El-Sadr told Infectious Disease News. “This was proof-of-concept that by [providing] antiretrovirals, you can decrease the amount of virus in the bloodstream and genital secretions, and consequently decrease transmission to the baby.”

These findings were followed by an observational study examining infection rates in more than 400 serodiscordant Ugandan couples. Published 1 year after HIVNET 012, the study showed that participants whose partners were infected demonstrated significantly higher mean HIV-1 RNA levels than those whose partners remained uninfected (90,254 copies/mL vs. 38,029 copies/mL; P = .01). Further, the researchers noted no new infections among HIV-negative patients whose partners had RNA levels of less than 1,500 copies/mL, and increasing bloodstream viral load was associated with greater risk for infection.

While these and other studies provided initial support for preventive treatment, El-Sadr said it was the HPTN 052 multisite randomized trial that clearly demonstrated the benefits of early ART. Initiated in 2005 and led by Myron S. Cohen, MD, professor of medicine and director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill, the study enrolled 1,763 serodiscordant couples from nine countries and randomly assigned either early or delayed ART. In 2011, an interim review of the results recommended by the study’s data and safety monitoring board showed a 96% relative reduction in linked transmissions resulting from early ART, and all remaining participants in the delayed ART arm were offered immediate ART initiation for continued study.

“Over another 5 years, most of the couples were followed, and they continued to show that when you treat the infected person, you drastically — virtually completely — reduce transmission,” Cohen told Infectious Disease News. “As all of this transpired — the realization that earlier treatment is lifesaving, that the amount of infrastructure needed is less than might be expected, that the price of the drugs fell. The treatment-as-prevention idea really took hold.”

Further research has continued to report favorable outcomes among virally suppressed patients. Preliminary results from the PARTNER study presented at CROI 2014 showed no new infections among 767 serodiscordant couples reporting condomless vaginal or anal sex. Although this data represented nearly 900 couple-years of follow-up and 44,500 sexual acts without condoms, updated findings from the full analysis will only be available after the study’s conclusion in 2017.

Treatment goals target new transmissions

In light of these findings and others suggesting numerous personal health benefits, immediate ART initiation is now recommended by the Department of Health and Human Services, WHO and various HIV health organizations. Along with the increasing availability of antiretroviral drugs, these endorsements have led to more people initiating treatment and achieving viral suppression than ever.

“At the turn of the millennium, there were less than a million people taking ART,” Godfrey-Faussett said. “Now we have almost 16 million people on antiretroviral drugs. That’s a massive increase. Nonetheless, we’re still quite a long way from reaching everybody.

“Last year, there were about 2 million new HIV infections. If we don’t get the number of new infections down, the number of people requiring treatment will continue to escalate. That puts an enormous burden on not only the budget, but also on doctors, nurses and health providers trying to keep so many people on treatment as we go forward.”

To increase the number of people receiving care and achieving viral suppression, UNAIDS launched its 90-90-90 treatment target in 2014. A campaign focusing on the cascade of HIV care, the program calls for 90% of all persons with HIV to be aware of their status, for 90% of those diagnosed to receive sustained ART, and for 90% of those receiving treatment to achieve viral suppression by 2020. Although he admitted that these are formidable targets, Godfrey-Faussett said the support his organization has seen since the announcement of the campaign is extremely encouraging.

“Many people say that what gets measured gets done,” Godfrey-Faussett said. “We’ve been very gratified at UNAIDS to see that since we brought out the 90-90-90 targets, many other organizations have joined us, and in many countries — particularly in countries severely affected by HIV. Governments have also made a commitment to aim for 90-90-90.”

Similar goals have been laid out under the White House’s National HIV/AIDS Strategy. Updated in July 2015, the strategy also aims to increase HIV diagnoses to 90% of the infected population, but seeks to increase linkage to care and viral suppression to 85% and 80% of the total U.S. HIV population — a slightly more aggressive target than that set by UNAIDS.

 

Eugene McCray, MD, director of the CDC’s Division of HIV/AIDS Prevention, said that while 87% of those with HIV in the U.S. already know their status, and more than 70% of those recently diagnosed are connected to care, achieving and maintaining these targets will be a challenge, especially with the country’s disproportionately affected black and gay populations.

“When we talk about the new strategy, and you look at the way the UNAIDS does theirs, we’re doing basically the same thing — it’s 90-90-90 for the U.S., essentially,” McCray told Infectious Disease News. “[The strategy] is very ambitious, and I think that with a lot of work we can get there. If we do, I think that we would begin to see dramatic decreases in the number of new infections that are being diagnosed in the U.S. and globally.”

Unfortunately, recent estimates for global ART coverage by 2020 published in PLoS Medicine suggest that the current international investment in TasP may be insufficient. According to the modeling analysis’ projections, many countries affected by the HIV epidemic would be unable to reach the 90-90-90 coverage target without both adopting new coverage interventions and committing more resources to the effort.

Regardless of whether these coverage goals are reached, Cohen noted that it is still uncertain to what extent these interventions may limit new HIV transmissions. Although he agreed that universal treatment should be pursued, he said that its full impact will likely depend on how effectively treatments are implemented.

“We’re in a window of time where we can’t see the magnitude of the public health benefit,” Cohen said. “It would be expected there would be some public health benefit, and there’s certainly a personal benefit, but the absolute magnitude is going to take a few years to understand. But then, if we fail to see the expected magnitude, it’s not because treatment doesn’t serve as prevention — it’s because we have to treat the right people at the right time with the right drugs to achieve suppression of viremia.”

Challenges throughout the cascade of care

Due to the multitiered goals of the 90-90-90 campaign, El-Sadr said to reach each target will require unique public health efforts.

“For every step of the HIV care cascade — from finding people who have HIV, to engaging them in care, to getting them on treatment, to keeping them on treatment, to keeping them virally suppressed — there can be gaps, and there are gaps,” El-Sadr said. “What we need to be thinking of is [how to] intervene in every step in order to reach the promise of ART for prevention.”

Although only 13% of those with HIV in the U.S. are unaware of their status, NIH estimates that this population is responsible for nearly one-third of all new infections. Worldwide estimates are more severe, with WHO estimating that only 54% of all people with HIV are aware of their status. According to Godfrey-Faussett, these shortcomings represent the biggest challenge to meeting the coverage goals for 2020.

“It’s still a very large number of people who don’t know their HIV status,” Godfrey-Faussett said. “In many places, HIV testing services are not yet agile enough to provide enough choices for people as to how they find out their HIV status, so not everybody goes to a clinic. We need to have HIV testing that is reaching out into the community, through pharmacies, [and with] the possibility of self-testing or testing at home.”

Testing and diagnosis is especially important within the first few months of a person’s infection, as Cohen and Volberding both said this is the time period when an individual’s high viral load makes them most contagious. As such, frequently testing those whose behavior may result in numerous transmission events could have a significant impact on HIV incidence.

“We know that a lot of transmission happens very early after a person becomes infected,” Volberding said. “If we can find people early in the infection and treat them, it will be good for them because we know that earlier treatment results in better maintenance of the immune system and CD4 counts, but it will also stop transmission at a time when viral load tends to be very high.”

However, even when a patient is diagnosed it can be difficult to begin treatment. Godfrey-Faussett said many people must be persuaded that antiretrovirals are best taken before the onset of severe illness, as opposed to being treated as a last resort, while El-Sadr noted that others simply do not wish to engage with health care.

To increase the number of diagnosed patients enrolled into care, a number of researchers are investigating what is known as a “test-and-treat” strategy. Often involving immediate enrollment in care upon a positive test result, several theoretical models — such as the one presented by Reuben M. Granich, MD, medical officer in the HIV/AIDS department of WHO, and colleagues in 2009 — have suggested that this form of aggressive enrollment could lead to reduced transmission. Although results have been mixed, additional studies currently underway in the U.S. and other countries could offer further data on this potentially effective intervention, McCray said.

“When somebody shows up and is diagnosed with HIV, you want to immediately get them on treatment, and when I say ‘immediately,’ I mean within a day, but no more than a week,” McCray said. “This test-and-treat strategy really is an attempt to capture people immediately, get them on treatment, and then to get them linked to their health care system.”

Many of these same challenges apply to retention and adherence. El-Sadr said patients who may initially seek out and enroll in treatment are often unable to remain in treatment due to a variety of circumstances, including substance use, lack of insurance, mental illness, poverty and homelessness. Godfrey-Faussett sympathized with these patients, and said more work is needed to remove the systemic barriers that make obtaining daily ART an inconvenience.

“Right now, when you start treatment, it’s a commitment to take it for life,” Godfrey-Faussett said. “It’s difficult for everybody to take tablets regularly, and if you don’t take your tablets regularly, then the virus usually springs back. We have to have systems that are much easier for filling prescriptions and distributing drugs to people who are well, and spend our medical time with the people who need medical attention who are unwell.”

Treatment disparities, stigma remain global issues

Volberding warned that due to a number of geographic and cultural factors, many of these efforts may not be implemented equally among those with the disease. He noted that much of the infrastructure in place to provide care is often focused in urban, resource-rich settings, an issue that McCray said is especially pronounced in the hardest-hit countries.

“The support systems that we have in the U.S. to support delivery of the drugs, or to support the individual patients who are taking the drug — those things don’t exist readily in the developing world,” McCray said. “They’re looking at a number of innovative ways to try and support people who are living with HIV so that they can stay on their drug, like using peer counselors ... but internationally this remains an important challenge.”

Godfrey-Faussett acknowledged the difficulties that these countries face, but stressed that many of the obstacles to care are universal, and require attention on all fronts.

“We need to be careful in assuming that [HIV care] is always more challenging in resource-limited settings,” Godfrey-Faussett said. “Of course it’s true that in poorer countries, there are fewer doctors, fewer nurses, fewer health care workers. Therefore, if they have a bigger burden, the patients often have to wait longer in queues, and then they have challenges with the drugs not being readily available every time they turn up.

“But even in countries like the U.S., there are many people who find accessing the health care system quite challenging as well, due to issues of insurance, or due to issues of stigmatization of HIV, or the way that the health care system treats them.”

Stigma, specifically, remains a serious challenge. According to Volberding, gender-based violence and sexual pressures rooted in stigmatization can keep persons with HIV in any country from seeking appropriate treatment. Godfrey-Faussett agreed and reminded providers not to become a part of the problem.

“We know that HIV disproportionately affects populations who are at the margins of society and often have difficult experiences in life because of criminalization, discrimination and stigmatization, and it’s difficult for these people to engage with health care services,” Godfrey-Faussett said. “But [engaging these populations] requires a change in attitude from health care workers as well. There is no doubt that stigma and discrimination, including from health care workers themselves, is an obstacle to HIV testing and to treating people with HIV correctly.”

Volberding added that public health groups must continue to develop “culturally sensitive” strategies to reach those most in need.

“Finding out where we still have pockets of high transmission, developing culturally appropriate strategies to reach people in those pockets, and along the way really beefing up the availability of care and removing access barriers are the important strategies,” Volberding said. “The strategy is to work with affected communities — for instance, here in San Francisco — and especially working in gay community organizations, with political figures, public health and academic people to rekindle awareness of HIV infection. However, we can’t expect that the same approach in one region will be effective in another region. We need to increasingly get this down to the community level where we can confirm some of these issues.”

Traditional prevention still a priority

Although increasing treatment may have a substantial impact on the number of new infections, Godfrey-Faussett said its success is heavily dependent upon other proven prevention methods.

“We can see that in the era of ART, some of the enthusiasm for condoms has been diminishing, and some of the funding for condom programs in poor settings hasn’t always been keeping up,” he said. “We should not let the treatment revolution distract us from the importance of old and new modalities of straightforward HIV prevention”

El-Sadr voiced a another concern, reminding health care providers that although transmission interruption is an important goal, it is first and foremost critical to provide care and protect the well-being of those with HIV.

“It’s really important for people with HIV to be on treatment for their own health, as well as for prevention,” El-Sadr said. “Some may perceive treatment-for-treatment and treatment-for-prevention as two distinct entities. They are completely connected and equally important.” – by Dave Muoio

• References:
• AIDS.gov. National HIV/AIDS Strategy for the United States: Updated to 2020. https://www.aids.gov/federal-resources/national-hiv-aids-strategy/nhas-update.pdf. Accessed February 16, 2016.
• Cohen MS, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1105243.
• Dutta A, et al. PLoS Med. 2015;doi:10.1371/journal.pmed.1001907.
• Granich RM, et al. Lancet. 2009;doi:10.1016/S0140-6736(08)61697-9.
• Guay LA, et al. Lancet. 1999;doi:10.1016/S0140-6736(99)80008-7.
• Rodger A, et al. Abstract 153LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston.
• National Institute of Allergy and Infectious Diseases. NIH Statement on World AIDS Day 2015. https://www.niaid.nih.gov/news/newsreleases/2015/Pages/WAD2015.aspx. Accessed February 16, 2016.
• Quinn TC, et al. N Engl J Med. 2000;doi:10.1056/NEJM200003303421303.
• UNAIDS. Joint United Nations Programme on HIV/AIDS. 90-90-90. www.unaids.org/en/resources/documents/2014/90-90-90. Accessed February 16, 2016.
• WHO. HIV/AIDS fact sheet. www.who.int/mediacentre/factsheets/fs360/en. Accessed February 16, 2016.

• For more information:
• Myron S. Cohen, MD, can be reached at mscohen@med.unc.edu.
• Wafaa M. El-Sadr, MD, MPH, can be reached at wme1@cumc.columbia.edu.
• Peter Godfrey-Faussett, MBBS, FRCP, can be reached at faussettp@unaids.org.
• Paul A. Volberding, MD, can be reached at paul.volberding@ucsf.edu.

Disclosures: Cohen, El-Sadr, Godfrey-Faussett, Granich, McCray and Volberding report no relevant financial disclosures. Please see the full studies for a list of the authors’ relevant financial disclosures.

PrEP prevents HIV, motivates people to seek services and decreases stigma.

PrEP drives progress toward the end of HIV transmission. Truvada (oral emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences) is safe and effective for preventing HIV acquisition when used. This possibility mobilizes people to obtain an HIV test, including people who believe they are HIV seronegative and people in denial due to paralyzing fear. PrEP also highlights that modern antiretroviral medications are safe; so safe that people living with HIV need not hesitate to take the medications that will save their lives. PrEP allows serodiscordant couples and people living with HIV another option for safer sex and safer conception. Seronegative gay men who tried to protect themselves by excluding the possibility of intimate contact with anyone who might be living with HIV may now feel safer to explore these relationships. Such bridging across the serological divide promises to increase familiarity with HIV, diminish stigma, foster belonging and replace serosorting with an effective prevention strategy.

PrEP is inspiring individual contemplation and research that will elucidate in detail the situations that involve exposure to HIV, situations that call for extra social support and resilience. So far, PrEP has attracted the right people at the right times to prevention and treatment services. This was most clearly demonstrated by the PROUD study, which found that people asking for PrEP had HIV incidence that was three to four times higher than expected based on their risk group. Demand for PrEP is exploding, and is now approved in the United States, France, Kenya, South Africa and Israel. By the end of 2015, 10% to 20% of gay men were taking PrEP in New York and San Francisco, and other cities are not far behind.

As PrEP scales up, HIV incidence plummets, a welcome change from rising transmission rates that occurred when demands for HIV epidemic control (eg, condoms and treatment) were mainly borne by people living with HIV. The PrEP era has arrived, enabling both testing and treatment strategies, and heralds the beginning of the end of HIV transmission.

• References:
• Auerbach JD, et al. J Int AIDS Soc. 2015;doi:10.7448/IAS.18.4.19983.
• Grant RM, et al. Abstract 25. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 23-26, 2015; Seattle.
• Grant RM, et al. Curr Opin HIV AIDS. 2016;doi:10.1097/COH.0000000000000216.

Robert M. Grant, MD, MPH, is a Betty Jean and Hiro Ogawa Endowed Investigator with the Gladstone Institutes in San Francisco. Disclosure: Grant reports contracts between his employer (the Gladstone Institutes), Gilead Sciences and ViiV Healthcare for research on long-acting injectable PrEP.

If scaled up, PrEP could be drive global prevention.

There are four main reasons why PrEP is a game changer.

First, PrEP complements current prevention strategies well. To reduce new HIV infections, we are already focusing on reducing the likelihood that those living with HIV will transmit it by treating people with HIV and reducing their viral load. PrEP complements this strategy by providing an effective approach to reduce the chance of acquiring HIV among those who aren’t currently infected.

 

Second, PrEP works well in the real world. Oral PrEP is rare in that it performed significantly better in the two large studies than in the initial efficacy study: both the PROUD and iPERGAY studies estimated 86% effectiveness, whereas iPrEx estimated 44% efficacy.

Third, many people who need PrEP are willing to take it. From Atlanta to South Africa, in demonstration studies and in our own studies of gay, bisexual and other MSM, a substantial proportion of at-risk men who are offered PrEP initiate the preventive treatment. 

Fourth, oral PrEP is only the beginning of the eventual benefits of this concept. Studies now underway might result in more options for medications and routes of delivery for people who could benefit from PrEP. Even with a vaccine, no single strategy will end new HIV infections; PrEP is an important part of a package of interventions that can get us much closer to that goal.

Patrick Sullivan, DVM, PhD, is a professor of epidemiology at the Rollins School of Public Health at Emory University. He can be reached at pssulli@emory.edu. Disclosure: Sullivan reports no relevant financial disclosures.

PrEP is only one of many necessary prevention tools.

The short answer is “no.” Although PrEP will be a component in the global prevention of HIV, it will be one of many tools that will contribute to the beginnings of global control of HIV. In addition to PrEP, we have treatment as prevention in which reduction of viral load to undetectable levels virtually eliminates transmission from the treated individual to others, so long as he or she remains on therapy. Other modalities include regular use of microbicides, condom use and education.

PrEP will likely be employed most among men who engage in higher-risk sexual activity with several partners per month. Barriers to the use of PrEP include access to evaluation, care and follow-up, medication cost and medication adherence, which is the rate-limiting step to the effectiveness of PrEP. Use of PrEP beyond higher-risk individuals raises several issues regarding the cost-benefit assessment of PrEP, including exposure of an uninfected individual to potential side effects of the intervention and use of resources, which include money and health system time, for low-yield protection.

We need to carefully assess each population for the best modalities to employ and the optimal timing and implementation of the interventions. Bending the epidemiologic curve of HIV will require strategic implementation of all of the prevention modalities in a thoughtful way.

Michael S. Saag, MD, is the director of the Center for AIDS Research at the University of Alabama at Birmingham. Disclosure: Saag reports consulting for Gilead Sciences and Merck, and receiving institutional grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare.