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We describe an HIV-infected patient with pre-treatment resistance to raltegravir, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, and the ultimate ability to achieve viral suppression. Pre-treatment integrase resistance testing is not routinely performed because transmitted integrase mutations conferring resistance to raltegravir are currently thought to be negligible. We suggest obtaining a pre-treatment integrase genotype in patients with transmitted multiclass drug resistance in order to create an optimal first regimen and increase the chance for virologic suppression.

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Purpose This review focuses on the recommendations for when to initiate antiretroviral therapy and what regimen to use in treatment-naïve patients based on the January 2011 antiretroviral guidelines released by the Department of Health and Human Services (DHHS). The evolution of recommendations over the past decade, key data supporting recent changes, and information related to management of antiretroviral therapy are discussed. Summary Treatment guidelines are updated frequently because of ongoing emergence of data demonstrating the risks and benefits of antiretroviral therapy. The DHHS guidelines strongly recommend initiating therapy in patients with certain conditions regardless of CD4 cell count and in patients with CD4 cell counts <350 cells/mm3. Although supporting data are less definitive, treatment is also recommended for patients with CD4 cell counts between 350–500 cells/mm3. Treatment for patients with CD4 cell counts >500 cells/mm3 is controversial. Although cumulative observational data and biological evidence support treatment at higher CD4 cell counts, randomized controlled trial data are not available, and the risk of antiretroviral toxicities, resistance, nonadherence, and cost should be considered in individual patients. The preferred regimens have been consolidated to four options, including a dual-nucleoside reverse transcriptase inhibitor backbone (tenofovir/emtricitabine) with a non-nucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir + ritonavir or darunavir + ritonavir), or an integrase strand transfer inhibitor (raltegravir). Regimens are classified as alternative or acceptable when they have potential safety or efficacy concerns, consist of higher pill burdens, or require more frequent dosing compared to preferred regimens. Conclusion The DHHS guidelines advocate earlier treatment initiation than recommended in recent years, yet recognize the limitations of the data supporting treatment at higher CD4 cell counts. Preferred regimens have been refined to maximize efficacy, safety, and quality of life for patients. The guidelines will continue to be updated as new data emerges.

Objective To identify an alternative inhaled corticosteroid to fluticasone propionate that can be safely coadministered with HIV protease inhibitors (PIs), we assessed the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, 17-monopropionate (17-BMP), in combination with ritonavir (RTV) and darunavir/ritonavir (DRV/r). Design Open label, prospective, randomized pharmacokinetic and pharmacodynamic study in healthy volunteers. Methods Thirty healthy volunteers received inhaled BDP 160 mcg BID for 14 days and were then randomized (1:1:1) into three groups: Group 1 (control) remained on BDP alone for 28 days; Group 2 received BDP + RTV 100 mg BID for 28 days, and Group 3 received BDP + DRV/r 600/100 mg BID for 28 days. Pharmacokinetic sampling for 17-BMP was performed on days 14 and 28, and pharmacokinetic parameter values were compared within patients and between groups. Cortisol stimulation testing was also performed on days 1, 14, 28, and 42 and compared within and between groups. Results Geometric mean ratios (day 28:day 14) (90% CI) for 17-BMP area under the concentration-time curve in groups 1, 2, and 3, respectively, were 0.93 (0.81–1.06, p=0.27), 2.08 (1.52–2.65; p=0.006), and 0.89 (0.68–1.09; p=0.61). There were no significant reductions in serum cortisol levels within or between groups (p>0.05). Conclusions DRV/r did not increase 17-BMP exposure, while RTV alone produced a statistically significant but clinically inconsequential 2-fold increase in 17-BMP exposure. Adrenal suppression was not observed in any of the study groups. These data suggest BDP can be safely coadministered with DRV/r and likely other RTV-boosted PIs.

Combination antiretroviral therapy (cART) has improved survival rates in HIV‐infected patients; however, patients now experience comorbidities that require pharmacological intervention, thereby increasing the risk of drug–drug interactions (DDIs). HIV protease inhibitors (PIs), non‐nucleoside reverse transcriptase inhibitors (NNRTIs), and the CCR5 antagonist maraviroc are primarily metabolized via the cytochrome P450 (CYP) system and are prone to pharmacokinetic interactions. 1,2 This article addresses some key challenges that prescribers face when using available drug interaction–data resources in making day‐to‐day clinical decisions. Clinical Pharmacology & Therapeutics (2010) 88 5, 712–719. doi:

Multiple direct-acting antiviral (DAA)-based regimens are now available for all hepatitis C virus (HCV) genotypes (GTs). Because HCV GT 4, 5 and 6 are less common in the United States (US) and worldwide, relatively small numbers of participants with these GTs were evaluated in individual clinical trials. To provide a comprehensive description of subtype diversity and treatment outcomes in clinical trials for these less common GTs, we analysed data from 744 participants with HCV GT4 (n = 573), GT5 (n = 81), or GT6 (n = 90) across 18 clinical trials of DAA regimens. These data are from US New Drug Applications submitted between 2014 and 2017, and our analyses included only approved regimens. Excluding unresolved or mixed subtypes, the distribution of reported GT4 subtypes was 49% 4a, 31% 4d and 16% for one of 14 other subtypes. The distribution of GT6 subtypes was 39% 6a, 27% 6e, 8% 6 L and 23% for one of 11 other subtypes. Across approved regimens, sustained virologic response rates 12 weeks post-treatment (SVR12) for GT 4, 5 and 6 ranged from 91% to 100%, 93% to 97% and 96% to 100%, respectively. SVR12 by GT4 subtype ranged from 96% to 100% for 4a and 81% to 100% for 4d. Virologic failures occurred in GT 4a, 4b, 4d and 4r. For GT6, SVR12 was 100% for all subtypes except 6 L, for which 1 of 7 participants experienced virologic failure. To our knowledge, this is the largest compilation of HCV GT 4, 5 or 6 clinical trial data. These analyses may be useful for clinicians treating HCV GT 4, 5 or 6.

Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient’s liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label–recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189 hours for maraviroc and 61 hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 14–18 hours and 9–12 hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48 hours for raltegravir. Unfortunately, the patient’s clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV-infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration-dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence-based approach to optimize dosage selection of these drugs in this patient population.