Editorial commentary: protease inhibitor monotherapy: safe for the CNS in durably suppressed patients?

(See the HIV/AIDS Major Article by Perez-Valero et al on pages 1627–34.) Since the advent of triple combination therapy (TCT) in the mid-1990s, antiretroviral drugs have gradually become more potent and less toxic. Today, providers still typically prescribe drugs in combinations of 3, in part because of strong evidence from randomized clinical trials of TCT that inform treatment guidelines; in part because of the simplicity of fixed-dose combinations that improve patient acceptance; and in part because of nearly 2 decades of clinical experience. For these reasons and others, many providers—particularly in the United States—do not routinely consider simplification of antiretroviral regimens in durably suppressed patients to just 1 or 2 drugs. However, adequately potent single- or dual-drug regimens that have sufficiently high genetic barriers-to-resistance have at least some advantages over traditional TCT, including lower cost and less toxicity. This may become even more evident with the graying of the human immunodeficiency virus (HIV) population because aging can result in changes in drug metabolism and disposition that could lead to late-onset adverse events. In addition to concerns about hastening development of antiretroviral drug resistance, one of the chief vulnerabilities of a single- or dual-drug treatment approach is the limited distribution of some antiretrovirals into protected compartments like the central nervous system (CNS). This vulnerability is mitigated when drugs are used in combination. However, when poorly distributed drugs are used alone, symptomatic or asymptomatic cerebrospinal fluid (CSF) viral escape can occur [1–3]. To better understand the effectiveness and limitations of antiretroviral monotherapy, Perez Valero and colleagues report in this issue of Clinical Infectious Diseases the findings of a prospective cohort study comparing protease inhibitor monotherapy (PMT) with either darunavir or lopinavir (each in combination with ritonavir) to typical protease inhibitor-containing TCT. The 134 participants had taken suppressive therapy for at least a year and were evaluated over time using a standardized 7-test battery that met recommended guidelines [4]. The principal finding was that the 2 treatment groups did not differ in neurocognitive functioning over 1 year of observation, providing reassurance that PMT does not increase the risk for HIV-associated neurocognitive disorder (HAND). The fact that >95% of both treatment groups maintained virologic suppression is also notable. Changing therapy for reasons other than virologic failure, however, was relatively common. The approximately 1 in 6 participants who changed regimens were more than twice as likely to take TCT than PMT (19 of 22 changing therapy vs 48 of 112 on stable therapy, relative risk 2.0, P < .001). To account for treatment discontinuations, the investigators performed both intent-to-treat and as-treated analyses and found consistent results. Clinical trials that compare antiretroviral drug regimens to neurocognitive functioning should ideally include several key elements. This cohort-based analysis included several, such as a longitudinal design, the use of standardized tests that assessed at least 5 cognitive abilities, the use of relevant normative data, and careful accounting for treatment changes. In contrast, 2 prior clinical trials of PMT were limited by using only brief assessments of neurocognitive functioning [3, 5]. These elements strengthen confidence in the current findings, although this confidence is undermined by multiple weaknesses. The most critical is the lack of randomization. This could be particularly influential because the treatment groups differed in several characteristics that could bias the findings. For example, compared with the TCT group, participants in the PMT group had substantially longer durations of antiretroviral therapy (by approximately 2-and-a-half years) and of virologic suppression (by nearly 2 years), which could result in survival bias favoring the PMT group. Adequate power is another critical element of successful clinical trials. Few participants progressed to neurocognitive decline, but the difference between the arms had a medium effect size in the direction of concern (5/44 (11.4%) PMT vs 3/45 (6.7%) TCT, relative risk 1.70). The small absolute risk is reassuring, but the effect size suggests that the project was underpowered to test this important difference. Clinical trials should also accurately assess all participants. In this study, TCT participants were less likely to be native Spaniards, which could result in worse performance on neurocognitive testing that has been adjusted for normative data from Madrid. If PMT was actually more detrimental to the CNS than TCT, this and other nonconservative biases could make it less apparent. The investigators do attempt to account for the impact of the between-group differences in multivariable analyses. In addition to addressing the safety of PMT, the analyses raise questions about the CNS penetration-effectiveness (CPE) approach to estimating antiretroviral drug effectiveness in the brain. Whether CPE—or any method of estimating drug distribution and efficacy in the CNS—is clinically relevant continues to be the subject of considerable debate. Discussions have focused more on the relationship between CPE and neurocognitive outcomes, for which the evidence is less consistent [6–10], than on the relationship between CPE and HIV RNA in CSF, for which the evidence is more consistent. In our prior analyses of HIV RNA in CSF, 2 observations were apparent: HIV RNA in plasma was the single most influential correlate of HIV RNA in CSF [11], and correlations between CPE and HIV RNA in CSF were strongest among people taking TCT [12]. Even though the susceptibility of some HIV protease inhibitors to CSF viral escape challenge the safety of the PMT approach, Perez Valero et al correctly apply these and other prior findings to counter that a PMT approach may be safe when the correct patient and the correct drug are selected. A patient who initiates therapy at a relatively high blood CD4+ T-cell count (eg, above 350 cells/mm3) and has durable virologic suppression (eg, >3 years) with very good immune recovery (eg, above 500 cells/mm3) may be an excellent candidate for PMT simplification. The ideal PMT drug should have both concentrations in the CNS that consistently and substantially exceed HIV inhibitory concentrations and a high genetic barrier to resistance (eg, darunavir or lopinavir in combination with a pharmacokinetic boosting drug). When using the right drug in the right patient, a PMT approach may successfully maintain virologic suppression while reducing adverse events and cost. Of note, even when virologic failure did occur during PMT in this analysis, no drug resistance-associated mutations were found, and all participants were successfully converted back to TCT. Overall, the findings support that patients who have been effectively treated for years may be successfully simplified to an appropriate PMT regimen without undue concern for virologic failure or neurocognitive decline. The current report stands as reassuring but insufficient by itself to adopt PMT into clinical practice. PMT simplification must be subjected to the rigors of an adequately powered, randomized, placebo-controlled clinical trial that builds on the lessons to date. One challenge moving forward will be the substantial funding that a sufficiently large clinical trial will require. As newer classes of antiretroviral drugs emerge and the field focuses on more intensive therapy to cure HIV, what organizations will fund clinical trials of less toxic and less costly therapy? For now, this remains an open question, but the issue is likely to grow in importance as treatment guidelines support earlier initiation of antiretroviral therapy; as more people with HIV enter clinical care, particularly in low-income countries; and as increasing numbers of patients live into their 6th decade and beyond.