Author Affiliations: Division of Infectious Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
More than 25 antiretroviral drugs and fixed-dose combinations have been approved by the US Food and Drug Administration for the treatment of human immunodeficiency virus (HIV) infection in the 2½ decades since zidovudine (ZDV) became the first drug approved for this purpose. These drugs now constitute 6 different classes, including nucleoside and nucleotide reverse-transcriptase inhibitors (NRTIs), nonnucleoside reverse-transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand-transfer inhibitors, fusion inhibitors, and entry inhibitors. When used in appropriate combinations (usually 2 NRTIs plus a third drug from another class), these drugs achieve sustained suppression of viral replication, resulting in the arrest of disease progression and reconstitution of immune function. Such combination antiretroviral therapy (cART) has resulted in dramatic declines in HIV-associated morbidity and mortality wherever treatment is accessible.1,2
Although newer antiretroviral drugs with improved potency, safety, tolerability, and convenience have replaced many older drugs, patients and providers are faced with an abundance of choice in selecting a particular cART regimen. In this issue of the Archives, Elzi et al3 explore the factors influencing choice of initial cART among adult patients followed up in the Swiss HIV Cohort Study (SHCS) as well as associated virologic and immunologic outcomes. They focused their study on participants who initiated cART after enrollment in the SHCS from January 1, 2005, through December 31, 2009. Nearly 2000 patients were included in this analysis; because a limited number of regimens are recommended for use in pregnant women, they were excluded.
The most commonly prescribed regimen was the combination of tenofovir (TDF), emtricitabine (FTC), and efavirenz, used by 29.9% of patients; TDF/FTC in combination with ritonavir-boosted lopinavir (lopinavir/r) used by 16.9% and in combination with atazanavir/r by 12.9% of patients; abacavir plus lamivudine (3TC) was used with efavirenz by 12.8%, and zidovudine (ZDV) plus 3TC with lopinavir/r by 5.8%. In the last 2 years of the study period, atazanavir/r use eclipsed lopinavir/r, and TDF/FTC with efavirenz and TDF/FTC with atazanavir/r became the most commonly used regimens. This trend accords well with patterns of cART use in the United States as well.
Overall, patients responded extremely well to cART, with 87.6% achieving virologic suppression to less than 50 copies/mL at 12 months. These impressive results mirror those obtained in clinical trials.4 Although an intent-to-treat analysis showed a trend toward better virologic outcomes in patients treated with TDF/FTC with efavirenz, no significant differences between the most commonly used regimens was observed in a multivariate analysis that controlled for a variety of potential confounders, including social and demographic characteristics, comorbidities, pretreatment viral load and CD4 cell count, prior AIDS diagnosis, clinic site, and calendar year. These data are reassuring in showing that patients can expect to do well regardless of which leading initial regimen they select.
As expected, a number of factors influenced the choice of initial regimen. For example, TDF/FTC-atazanavir/r was more likely to be used than TDF/FTC-efavirenz in patients with depressive disorders (presumably because of concerns regarding central nervous system adverse effects of efavirenz) and in those receiving opiate substitutes (presumably because of adverse drug-drug interactions between opiate substitutes and efavirenz). The more common use of ZDV/3TC-lopinavir/r in women may be explained by a desire to avoid potential teratogenic effects of efavirenz in women of childbearing age. In addition, ZDV/3TC-lopinavir/r is the preferred regimen for treatment of HIV in pregnancy,5 and physicians may have anticipated that a certain number of their female patients would become pregnant.
Other patterns of regimen choice are puzzling and less easily explained on the basis of treatment guidelines or data. The more frequent use of TDF/FTC-lopinavir/r in patients with a prior AIDS diagnosis or viral load higher than 100 000 copies/mL appears to be rooted in the persistent belief among physicians that ritonavir-boosted PI regimens are more potent than NNRTI-based regimens, empirical evidence notwithstanding.6,7 Paradoxically, patients with CD4 cell counts greater than 350 cells/mm3 were less likely to start a TDF/FTC-efavirenz regimen than a PI-based regimen. In addition, choice of regimen varied significantly by clinic site. Unless explainable by differences in baseline clinical characteristics of patients, such differences suggest significant regional variation in how different groups of patients and physicians interpret the same set of data regarding the efficacy, safety, and tolerability of different cART regimens.
Despite the general success of cART in the SHCS population, it is noteworthy that more than 30% of patients switched their initial regimen during the first year, and 12% interrupted cART for at least 4 weeks. Regimen changes were significantly more common among patients started on ZDV/3TC-lopinavir/r, which may have more treatment-related adverse effects than other regimens commonly used by patients in the cohort. Adjusted analyses that controlled for sociodemographic and clinical factors found that women, patients with CD4 cell counts higher than 350 cells/mm3, and those initiating a lopinavir/r-containing cART were most likely to change regimens. Although it is reassuring that most patients achieved viral suppression despite the relatively high proportion of patients switching therapy, these data make clear that one size does not fit all and emphasize the importance of individualizing the approach to cART.
This study has a number of important strengths, including the comprehensive data collected by the SHCS, the relatively large number of patients studied, and the analysis of a period that is reasonably contemporary. The large preponderance of white men in the study population, however, may limit the generalizability of the data to other less affluent settings with more diverse populations. In addition, as noted by the authors, too few patients had received newer regimens, including darunavir/r or integrase inhibitors, to be included in the analysis. Similarly, data are lacking from this cohort on initial cART regimens that include entry inhibitors. A number of factors not included in the analysis might have shed additional light on the rationale for certain regimen choices, including, for example, physician experience (years of treating HIV) and practice setting (urban/rural and academic/private). It would also be interesting to know whether regimen cost played a role in the choice of regimen (or in the range of regimens available).
With the recent approval of rilpivirine8 and the anticipated approval of cobicistat-boosted elvitegravir,9 the choices for first-line cART continue to expand. As current first-line regimens become generic and less expensive, pressure will mount to provide outcomes data to guide patients, clinicians, and payers in selecting appropriate cART. Additional studies such as this one, along with rigorously conducted randomized clinical trials comparing first-line cART regimens, will be needed to provide that guidance.
Correspondence: Dr Kuritzkes, Division of Infectious Diseases, Brigham and Women's Hospital, 65 Landsdowne St, Room 449, Cambridge, MA 02139 (firstname.lastname@example.org).
Published Online: August 13, 2012. doi:10.1001/archinternmed.2012.3644
Financial Disclosure: Dr Kuritzkes reports that he is a consultant to Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Roche, and ViiV; he has received research grant support from Gilead and Merck; and he has received speaking honoraria from Gilead and Roche.
Funding/Support: This invited commentary was supported in part by grants UM1 AI068636 and U01 AI069472 from the National Institutes of Health.
Kuritzkes DR. An Abundance of ChoicesComment on “Choice of Initial Combination Antiretroviral Therapy in Individuals With HIV Infection: Determinants and Outcomes”. Arch Intern Med. 2012;172(17):1321-1323. doi:10.1001/archinternmed.2012.3644