Hopkins Global Health Leadership Fellow, Alex Billioux, shares his list of key papers in HIV Research

May 16, 2014

 

As an Afya Bora Fellow in Global Health Leadership at Johns Hopkins, I have sought to identify the key papers that changed the way the scientific community—and in many cases, the world—viewed HIV, its prevention, and treatment.  What follows is by no means a comprehensive list of all the major papers in HIV research as that list would be too large to be useful and would inevitably miss out on a number of important publications.

The first paper was the first public signal of the AIDS epidemic. This is the Center for Disease Control’s MMWR (Morbidity and Mortality Weekly Report) of 5 homosexual men in LA found to have a rare fungal pneumonia, pneumocystis pneumonia (PCP; first published AIDS cases).

Next we have the first academic article (published by same authors) describing the loss of cellular immunity typifying AIDS

Next we have two papers, the first by Luc Montagnier’s group in France and the second by Robert Gallo’s group in the US describing the isolation of the human immunodeficiency virus.  

Living in the era of antiretroviral medications, we often forget how scary the early days of HIV were. Though I was young, I remember vividly the panic associated with HIV that sparked national discussions on whether people living with HIV should be quarantined or allowed to continue to work and go to school. The fear and stigma surrounding HIV began to slowly decrease after the publication of this paper demonstrating the utility of AZT as the first drug to treat HIV infection.

Unfortunately, less than two years later this paper came out indicating that HIV in patients treated with AZT alone was rapidly developing resistance to AZT, making the drug ineffective. 

In response to this demonstration of rapid development of HIV resistance to antiretroviral monotherapy, groups began to combine antiretroviral drugs fresh from the FDA pipeline in the hope that using more than one drug would reduce the chances for HIV to develop resistance before the drugs had a chance to suppress the virus in the blood. This treatment trial conducted by Roy Gulick and colleagues compared treatment regimens consisting of a single protease inhibitor (PI; in this case indinavir), two nucleoside analogue reverse transcriptase inhibitors (NRTIs; zidovudine and lamivudine), and a combination of all three drugs. This study was instrumental in ushering in the era of Highly Active Antiretroviral Therapy (HAART) and setting one of the key paradigms of HIV treatment employed to this day(i.e., combination of two NRTIs with either a PI or a non-nucleoside reverse transciptase inhibitor)

Unfortunately, less than 2 months later Robert Silicano’s group demonstrated that despite suppression of HIV in the serum of patient’s on HAART, virus could still be detected and amplified in resting latent T-cells. This reservoir of HIV in resting cells is the reason that long-term treatment with antiretroviral drugs does not fully eradicate the virus from infected individuals

Having proven the efficacy of HAART in the suppression of HIV replication and development of AIDS, the next key question was when to initiate therapy. As early treatment regimens carried numerous annoying and sometimes dangerous side effects, HAART was held until an individual’s CD4 count reached 200 cells/mm3 or she developed an AIDS-defining illness such as PCP. However, a landmark retrospective study of patients in the NA-ACCORD database demonstrated a survival benefit to initiation of HAARTat or above 500 cells/mm3. This study eventually led to the current policy in most high-income countries of initiating HAART as soon as possible after diagnosis of HIV. 

While these dramatic advances were taking place in the treatment of HIV in high-income countries, a different story was evolving for the epidemic in low- and middle-income countries. In Africa, where simian immunodeficiency virus (SIV) jumped to humans in the early twentieth century resulting in the main HIV-1 epidemic, AIDS went largely unrecognized until a Ugandan group described the identification of HIV in a group of patients who had been suffering from a mysterious wasting disease called “Slim disease”. This paper would set off a chain of similar investigations throughout the continent that would begin to reveal the scale of the HIV epidemic in sub-Saharan Africa which would ultimately result in a new global focus on HIV.

This same group working in Uganda subsequently undertook one of the first (and to this day longest-lasting) cohort studies of HIV in Africa, demonstrating that unlike the Western epidemic that was largely centered among men who have sex with men (MSM), injection drug users (IDU), and individuals exposed to large volumes of blood products before the blood supplies were routinely screened for HIV; the main method of transmission in Africa was through heterosexual sex. The risk of HIV infection was found to be related to proximity to trading centers and by the number of sexual partners.

During the early epidemic, HAART was too costly for most low- and middle-income countries so the focus in these regions was on reducing the risk of viral transmission. One major area of interest was in decreasing transmission of HIV from mother to child. Initially only preventive methods (such as avoiding long labor, delivery by cesarean section and refraining from breast-feeding) were available, but the landmark ACTG 076 study demonstrated the benefit of a short course of zidovudine therapy during and after pregnancy in reducing vertical HIV transmission.  

Another key focus for prevention was reduction of HIV transmission among heterosexual couples. In 2006 and 2007, three separate landmark clinical trials (South AfricaUganda & Kenya) demonstrated the efficacy of medical male circumcision (MMC) in the prevention of HIV transmission, reducing the risk by roughly 60%. These studies led the World Health Organization (WHO) and CDC to prioritize MMC among sexually active men in endemic countries (especially sub-Saharan Africa).

Perhaps the most important of the HIV prevention trials to date was the HPTN 052 study. This very large, multi-center trial conducted in the US and a number of low- and middle-income countries demonstrated a 96% reduction in transmission of HIV among serodiscordant couples (couples in which one partner is infected with HIV and the other is not) when the HIV infected partner was treated with HAART immediately after enrollment rather than waiting for a decline in CD4 count below 250 cells/mm3. This paper is one of the key bases for the development of the ‘treatment as prevention’ strategy which argues that the most effective preventive strategy is to treat all HIV infected individuals to suppress their viral loads and dramatically reduce the likelihood of transmission through bodily fluids.

One of the most recent advances in HIV prevention is the administration of antiretroviral medications to uninfected individuals who are at high-risk for HIV infection, a strategy termed pre-exposure prophylaxis (PrEP). While three trials have clearly demonstrated the efficacy of this strategy (iPreX study of PrEP in MSMPartners PrEP study among heterosexual couples &TDF2 study of PrEP among heterosexual couples), the Fem-PrEP trial evaluating this strategy in heterosexual African women not necessarily in long-term relationships demonstrated no benefit. The Fem-PrEP findings have been attributed to the fact that women in this study might not have been taking their PrEP regularly while in-between sexual relationships or took the medication only after initiating a new sexual relationship, both resulting in a reduced likelihood of effectively preventing infection. These studies resulted in FDA approval of tenofovir-emtracitabine (the main drug tested in the PrEP studies) for prophylactic use in individuals at high-risk for HIV infection, but the Fem-PrEP study has dampened support for this strategy in the general population.

Despite these successes in treatment and prevention of HIV, the development of a widely reproducible cure for the infection (with most hopes pinned on a neutralizing vaccine) have thus far been unsuccessful. To date only two individuals have been declared cured of HIV infection. The first was the so-called Berlin patient, an HIV-infected man who developed acute myeloid leukemia and who underwent bone marrow transplantation in 2006 from a donor with a CCR5 delta32 mutation (a mutation in a key cell surface protein necessary for HIV entry into T-cells that renders the virus unable to infect these cells). After successful engraftment of the donor’s bone marrow, HAART was discontinued and repeated attempts to find HIV in his blood have detected no virus

The second HIV ‘cure’ was an infant born to an HIV-infected mother and treated with antiretrovirals early after birth because of risk of exposure. Initial laboratory studies indicated the infant had been infected with HIV in utero and so the infant was treated with three antiretrovirals rather than the standard two-drug regimen. The child received this cocktail for 18 months, but then the child and her mother failed to come to follow-up clinic visits for 5 months. When they were finally recovered in care, the infant no longer had any detectable virus in her blood. Thus far, subsequent attempts to detect virus have found no HIV in the blood. Recently a second infant with a similar clinical course to this child has also tentatively been declared cured of HIV, but more time is necessary to support this claim. As a result, a large trial in which early triple-drug HAART is administered to at-risk infants born to HIV infected mothers is being planned to evaluate the generalizability of this approach as a treatment strategy.