THIRTY YEARS OF HIV AND AIDS: Edited by David A. Cooper and Giuseppe Pantaleo
Thirty years is not a long time in the history of a disease. However, the past three decades have seen the most intensive investigation and research into HIV of any disease known to mankind. During this time, the impact of combination antiretroviral therapies (ARTs) on the HIV pandemic cannot be underestimated and stands as one of the modern miracles of medicine, saving millions of lives around the world.
Nevertheless, many questions remain to be answered; some may remain beyond the reach of current knowledge and others fall into the fields of policy and economics. If you had the power to make it happen within an ethical framework, would you enable testing and subsequent treatment of every person in your country found to be HIV-infected? If yours is a generalized epidemic, you might decide that this is the most effective form of program of test and treat to contain the epidemic. Or you might choose to engage all members of your risk groups – assuming you know who they are – and test them and their partners, if your epidemic is concentrated and not yet in the broader population. Of course, cost will always be an object and a factor in such policy decisions.
Thirty years of intensive examination of the natural history of HIV, through large cohorts such as EUROCOORD and International epidemiologic Databases to Evaluate AIDS (IeDEA), have defined dramatically improved survival and outcomes. In the post-ART era, serious non-AIDS events such as cancer and heart disease are increasingly seen in our HIV-infected populations. However, cohort analyses have thrown up conflicting results on questions of when to start ART and therefore randomized clinical trials such as The Strategic Timing of Antiretroviral Therapy (START) are ultimately the only way to answer this question.
Each step forward creates more questions to be answered. Recent advances in the area of HIV latency have encouraged cautious hope that the eradication of the DNA virus might in fact be possible, and international consortia are working on strategies to ‘wake up’ latent virus and at the same time harness the immune system to kill it. This remarkable advance may give us a possible avenue for therapeutic vaccines, but it will also demand the urgent development of the near-impossible: a standardized assay that can reliably diagnose the complete absence of disease.
Major advances have been achieved in the delineation of HIV-specific immune responses. However, the identification of immune correlates of protection from HIV infection is still lacking. Genetic factors and particularly human leukocyte antigen (HLA) class I alleles such as HLA-B*5701 represent the strongest correlate of protection from HIV infection. Functional profiles, that is polyfunctional profiles, and the specificity, that is T-cell responses specific to Gag, of CD4+ and CD8+ T-cell responses are immunological markers associated with nonprogressive infection. However, broad neutralizing antibodies which are detected 3–4 years after infection show no efficacy in the control of HIV replication. Therefore, development of effective HIV-specific T-cell immunity is critical in the control of HIV chronic infection.
The RV144 trial has shown for the first time that an HIV vaccine is able to prevent (although the protective effect remains modest, i.e. 31%) acquisition of HIV infection. New insights into the identification of immune correlates of protection have indicated a potential role of binding IgG antibodies in preventing HIV infection. Several new vaccine approaches are currently being developed that show substantial improvement in the potency and breadth of T-cell responses. New targets of broad neutralizing antibodies have been identified and major advances are being made in designing novel envelope immunogens to induce broad neutralizing antibodies.
In the absence of an effective vaccine, ART remains the mainstay of our approach and is the foundation of a range of creative responses to HIV infection. The recent Treatment as Prevention (TasP) trial, HIV Prevention Trials Network (HPTN052), has stimulated the field and encouraged us to believe that a more widespread implementation of ART could turn around the epidemic in some countries. The benefits of TasP are clearcut, but the unanswered question here is the level of CD4+ cell count at which we start treatment. We know that treatment is beneficial for personal health outcomes for persons with moderate and severe immunodeficiency, but is there enough evidence to implement ART regardless of the disease stage on the basis of the public health approach? Questions of human rights and of personal autonomy in making health choices also arise.
The widespread implementation of test and treat could bring about reduced incidence and increased costs. Methods of keeping costs contained include treatment optimization, for which current studies are promising; cheaper and less frequent monitoring; and strategies of task-shifting from first-line healthcare workers to other staff able to deliver healthcare in remote settings. This would have the added advantage of higher patient compliance through reduced travel obstacles to collect drug supplies.
Each step forward in the advance against HIV brings us to a crossroad, a point where a decision is needed about the direction in which to proceed. ART is well established as an important tool for treatment and prevention; however, it is very likely that the provision of ART for 34 million people is unsustainable in the long term. In 30 years we have gone from warnings of the black plague, even in reputable publications, to advocating the real possibility of eradication. But until that is a reality, and in the continuing absence of a vaccine or an effective microbicide, effective utilization of ART and proven biomedical prevention techniques including male circumcision, targeted Pre-Exposure Prophylaxis (PREP) and ART for serodiscordant couples must remain a very high priority.
Conflicts of interest
There are no conflicts of interest.