Thirty years of treating HIV-1 infection: where next?

Abstract

Images of multi-coloured quilts laid out at the Washington Memorial or on New York’s Governor’s Island commemorating those who have died from HIV infection serve as a reminder that years after the 1981 report by Gottlieb, which signalled the start of the HIV pandemic, there is still much to do. The five reported individuals with Pneumocystis jiroveci pneumonia heralded over 70 million global HIV infections. Today, an estimated 35 million live with HIV, the majority—but by no means all—in sub-Saharan Africa. The introduction of three-drug combination antiretroviral therapy (ART) in the mid-1990s resulted in sustained viral inhibition and preservation of CD4 T cell function. As a result, progression to AIDS is preventable, leading Hilary Clinton to call in 2012 for an ‘AIDS free generation’. From being an almost invariably fatal infection, a newly diagnosed HIV positive individual starting ART now has a life expectancy equivalent to a matched HIV negative person. Additionally, the HIV negative partner of an infected person taking ART is protected from infection. This concept of ‘treatment for prevention’ is gaining traction with large-scale community-wide ‘test and treat’ studies such as HPTN071 PopArt (in South Africa and Zambia) or SEARCH (in Uganda and Kenya), in which the broader capacity and public health benefit of ART on HIV incidence can be assessed. Prophylactic ART can also help prevent infection in HIV negative individuals at high risk of HIV exposure. Such ‘pre-exposure prophylaxis’ has been approved by the Food and Drug Administration (FDA) with Truvada (a combination of two reverse transcriptase inhibitors, emtricitabine and tenofovir) now licensed for this use. The global provision of ART to eligible individuals among the 35 million living with HIV remains a challenge, especially in resource-limited regions. UNAIDS estimates that as of mid-2014, 13.6 million people were receiving ART with over $19 billion invested in the AIDS response in lowand middle-income countries. Meeting the ‘90-90-90’ target (90% of infected individuals knowing their status, 90% of these on ART and 90% of these with undetectable viraemia) set for 2020 remains a major undertaking. Tackling issues around prevention, reducing stigma and bigotry, and providing resilience for health care services to sustain delivery of care for the future are issues that go hand-in-hand with ART provision. ART is not a cure. HIV spreads widely in the human body during the early days of infection. With ART, the amount of virus declines dramatically but a tiny residual set of infected cells containing viral DNA remains detectable. On stopping ART, these cells can activate, resulting in the transcription and translation of viral nucleic acid into new virions, restoring the original disease state. The clear parallel is with the ‘minimum residual disease’ model for cancer. Cells harbouring residual viral DNA have dormant qualities— these cells comprise the ‘latent reservoir’. HIV DNA can be detected in tissues such as blood, lymph nodes, gut, genitourinary tract and brain, and even preferentially within certain CD4 T cell subsets. In the search for an HIV cure, there remains only a single successful case, that of Timothy Ray Brown. Cured by a CCR5 delta32 HIV-resistant stem cell transplant as part of treatment for acute myeloid leukaemia, Brown remains well and aviraemic 7 years later, with no evidence of a persisting viral reservoir. This case is set in context by six subsequent CCR5 delta32 stem cell transplants, which all resulted in the deaths of their HIV positive recipients. So, although a remarkable proof-of-principle, this case of cure remains an isolated, unrepresentative, one-off. More tantalising are cases of ‘post treatment control’ (PTC) as well as early evidence that certain agents, such as histone deacetylase inhibitors (HDACi) and protein kinase C agonists, can reverse HIV latency, turning the viral reservoir into a potential target. PTC is intriguing. Originally reported in a group of French patients, the VISCONTI cohort, the early administration of ART within weeks of infection subsequently allowed patients to stop therapy and remain aviraemic. Although there is evidence of detectable, although very low, HIV reservoirs in these patients, some have remained off therapy for years without viral resurgence or CD4 T cell decline. The mechanism underpinning this is not clear, but looks different to that protecting the ‘elite controllers’—