Yhoctrongcuocsong: The Evolution of HIV Management

By Michael Broder, PhD
Reviewed by Mark Wainberg, PhD, Director, McGill University AIDS Centre, Montreal, Quebec, Canada

Before the development of antiretroviral therapy (ART), before the human immunodeficiency virus (HIV) was identified as the virus that caused AIDS, and before AIDS was recognized as a discrete medical syndrome, there were reports of unusual and inexplicable outbreaks of conditions that were usually associated with immune compromise. These included conditions such as Pneumocystis carinii pneumonia (PCP) and Kaposi’s sarcoma (KS), both observed in cohorts of gay men in the summer of 1981. The constellation of opportunistic diseases associated with immune deficiency in otherwise healthy gay men came to be called Gay-Related Immune Deficiency (GRID). Subsequently, the same type of deficiency was observed in other groups, including injection drug users, blood transfusion recipients, hemophiliacs, and Haitian immigrants, as well as infants and the female sexual partners of affected men. Because the condition clearly was not gay-specific, public health officials changed its designation to Acquired Immune Deficiency Syndrome (AIDS). It appeared to be sexually transmitted, but causality initially was unknown.
In addition to PCP and KS, other opportunistic infections (OIs) were soon observed, including mycobacterial infections, toxoplasmosis, invasive fungal infections, and non-Hodgkin’s lymphoma.¹ Treatments were available for some OIs, including PCP² and KS,³ but not for others; for example, in the case of cryptosporidiosis, the only available treatment was palliative therapy with antimotility agents that were not consistently effective.²
Beginning in 1989, the US Department of Health and Human Services (DHHS) issued a series of guidelines for preventing common OIs, including PCP and Mycobacterium avium complex (MAC).² By 1995, these guidelines covered the prevention of all HIV-related OIs.²
By the early 1990s, advances in OI management led to improved quality of life and increased survival among people with HIV/AIDS. However, it was only with the widespread use of ART, beginning in the mid-1990s, that HIV infection became a chronic, manageable condition. A dramatic reduction in OI-related morbidity and mortality has been observed among patients who have access to ART.²
The road to widespread and effective ART treatments was a winding one. Once HIV, a retrovirus, was identified as the causative agent of AIDS in 1983, the race was on to find effective antiretroviral therapies targeting 1 or more stages in the HIV lifecycle.⁴ The first target to be effectively exploited was the HIV reverse transcriptase (RT), an enzyme responsible for converting viral RNA into DNA within an infected cell.⁵ The first nucleoside reverse transcriptase inhibitor (NRTI) was zidovudine (ZDV), approved by the US Food and Drug Administration (FDA) in 1987. Over time, clinical trials showed a survival benefit with ZDV monotherapy in patients with symptomatic HIV infection, but not in asymptomatic infection.⁶ Moreover, any survival benefit was measured in months rather than years, due to the emergence of viral resistance to the drug.⁶
The first combination to show a survival benefit in both symptomatic and asymptomatic patients was ZDV/3TC.⁹ Nevertheless, dual combination therapy with NRTIs, like NRTI monotherapy, proved to be limited by the emergence of resistance.
The turning point came in 1996, with the emergence of 2 new classes of antiretroviral agents. The protease inhibitors (PI) targeted HIV protease, an enzyme responsible for processing viral polyproteins essential to viral maturation.¹ Nonnucleoside reverse transcriptase inhibitors (NNRTIs), like the NRTIs, target HIV RT, but via a different mechanism of action. At the XI International AIDS Conference in Vancouver in July 1996, attendees were astounded by the presentation of results from clinical trials of triple-combination therapy, using dual-NRTI “backbones” in combination with a “third agent,” that was either a PI or an NNRTI. These triple-combinations regimens were considerably more potent than dual-NRTI therapy and were referred to as maximally suppressive regimens or highly active antiretroviral therapy (HAART). In addition to the clinical benefit provided, by eliminating detectable virus from the peripheral blood, these regimens delayed or prevented the emergence of drug-resistant viruses, increasing the durability of treatment.
At first, the data from clinical trials favored PI-based regimens over NNRTI-based regimens.¹¹. When DHHS issued the first guidelines for ART in April 1998, the preferred approach to therapy was to combine one of the available PIs (indinavir, nelfinavir, saquinavir, or ritonavir) with an appropriate dual-NRTI backbone. These included ZDV/ddl, d4T/ddl, ZDV/ddC, ZDV/3TC, and d4T/3TC.¹.
By the end of 1998, the newly approved NNRTI efavirenz was included among the list of preferred third agents.¹². Subsequently, ddI/3TC was added to the list of preferred NRTI backbones and ddC came off the strongly recommended list because of toxicity.¹³ Studies also showed that ddC did not combine well with other available NRTIs, and it was subsequently withdrawn from the market.¹⁴
In the ensuing years, pharmacologic boosting of PIs with subtherapeutic doses of ritonavir, a potent inhibitor of the cytochrome P450 pathway, became routine. Lopinavir (LPV), approved by the FDA in 2000, was the first PI to be coformulated with ritonavir (LPV/r, the small “r” being used to indicate subtherapeutic doses of ritonavir as a pharmacologic booster).
The 2003 recommendations were simplified but gave clinicians more choices in mixing and matching elements of the NRTI backbone. Preferred NNRTI-based regimens included efavirenz plus 3TC combined with ZDV, d4T, or tenofovir disoproxil fumarate (TDF), the first nucleotide RTI, approved by the FDA in 2001. Preferred PI-based regimens included LPV/r combined with 3TC and either ZDV or d4T.¹⁵ In 2004, a new NRTI, emtricitabine (FTC), approved by the FDA in 2003, was recognized in the guidelines as interchangeable with 3TC,¹⁶ of which it was a fluorinated derivative.¹⁷ At the same time, d4T was demoted from preferred to alternative status due to increasing reports of d4T-related toxicities.¹⁶
Beginning with the October 2006 guidelines, the preferred dual-NRTI backbones were the coformulated forms of TDF/FTC and ZDV/3TC.¹⁸.
In January 2008, another coformulated dual-NRTI backbone joined the preferred list: abacavir (ABC)/3TC. The FDA approved ABC in 1998. Coformulated ZDV/3TC moved from the preferred list to the alternative list, largely because of ZDV-related toxicity. The preference for ABC/3TC, however, was short-lived, as the November 2008 edition of the guidelines listed only TDF/FTC as preferred. ABC/3TC became an alternative because of data showing a higher rate of virologic failure in patients who initiated treatment with an ABC/3TC-containing regimen with a baseline HIV RNA level (viral load) of >100,000 copies/mL in a study termed ACTG 5202.¹⁹ Also concerning were data from multiple studies suggesting an association between ABC use and elevated risk for cardiovascular disease, even though there is still no consensus that such an association truly exists.¹⁹
The first HIV integrase strand transfer inhibitor (INSTI), raltegravir (RAL), was approved by the FDA in 2007. HIV uses the integrase enzyme to integrate viral DNA into the DNA of infected cells, an essential step in HIV replication.²⁰ Two more INSTIs were approved in 2012 (elvitegravir, EVG) and 2013 (dolutegravir, DTG). EVG needs to be pharmacologically boosted by a newly developed boosting agent termed cobicistat (cobi).
Since 2009, the guidelines have recommended complete regimens, moving away from the idea of recommended dual-NRTI backbones and recommended PIs, NNRTIs, or INSTIs presented in a mix-and-match format. The currently recommended regimens include 4 INSTI-based regimens: DTG/ABC/3TC (coformulated); DTG plus TDF/FTC (the NRTI backbone is coformulated); RAL plus TDF/FTC (the NRTI backbone is coformulated), and EVG/c/TDF/FTC (coformulated; the lower-case c indicates the use of cobi). Also included is one boosted-PI–based regimen, DRV/r plus TDF/FTC (the NRTI-backbone is coformulated; the lower-case r indicates the subtherapeutic dose of ritonavir used for pharmacologic boosting). ²¹

Published: 09/29/2015
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Thứ Hai, 7 tháng 3, 2016

The Evolution of HIV Management

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