Ighovwerha Ofotokun

Efficacy and Tolerability of 3 Nonnucleoside Reverse Transcriptase Inhibitor–Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1: A Randomized, Controlled Equivalence Trial

Background Non-nucleoside reverse transcriptase (NNRTI) inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.BACKGROUND Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING 57 sites in the United States and Puerto Rico. PATIENTS Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION The trial was open-label, and ritonavir was not provided. CONCLUSION Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases.

Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats.

Osteoporosis and bone fractures are increasingly recognized complications of HIV-1 infection. Although antiretroviral therapy itself has complex effects on bone turnover, it is now evident that the majority of HIV-infected individuals already exhibit reduced bone mineral density before therapy. The mechanisms responsible are likely multifactorial and have been difficult to delineate in humans. The HIV-1 transgenic rat recapitulates many key features of human AIDS. We now demonstrate that, like their human counterparts, HIV-1 transgenic rats undergo severe osteoclastic bone resorption, a consequence of an imbalance in the ratio of receptor activator of NF-κB ligand, the key osteoclastogenic cytokine, to that of its physiological decoy receptor osteoprotegerin. This imbalance stemmed from a switch in production of osteoprotegerin to that of receptor activator of NF-κB ligand by B cells, and was further compounded by a significantly elevated number of osteoclast precursors. With the advancing age of individuals living with HIV/AIDS, low bone mineral density associated with HIV infection is likely to collide with the pathophysiology of skeletal aging, leading to increased fracture risk. Understanding the mechanisms driving bone loss in HIV-infected individuals will be critical to developing effective therapeutic strategies.

Antiretroviral Pharmacokinetic Profile: A Review of Sex Differences

BACKGROUND Emerging evidence suggests that female sex may be associated with increased risk of developing antiretroviral toxicities. Although the mechanisms of sex-related antiretroviral pharmacodynamic differences remain poorly understood and may be multifactorial, they appear to be mediated through a common pathway of pharmacokinetic variability between the sexes. OBJECTIVE This article reviews sex differences in the pharmacokinetics of the major classes of antiretroviral drugs currently approved for HIV treatment by the US Food and Drug Administration, identifies knowledge gaps, and provides recommendations for future research directions. METHODS To identify pertinent articles for this review, the MEDLINE database was searched from 1990 to June 2006 using the terms sex, gender, antiretroviral therapy, ART, HAART, pharmacokinetics, pharmacodynamics, NRTI, NNRTI, and protease inhibitors. Search results were restricted to English language and human studies. The reference lists of identified articles were also used, as well as abstracts from relevant conferences. In addition, individual antiretroviral drugs were searched by sex/gender or by pharmacokinetics. RESULTS Current evidence, though limited, does suggest the existence of a sex disparity in antiretroviral pharmacokinetics, and such disparity has been shown to have pharmacodynamic implications for some drugs. Sex-mediated intracellular pharmaco-enhancement was associated with superior antiviral activities for the zidovudine and lamivudine members of the nucleoside reverse transcriptase inhibitor class. There appears to be divergent opinions about whether sex is a significant determinant of either nevirapine or efavirenz plasma concentrations. For certain protease inhibitors (PIs) (eg, saquinavir [SQV] and indinavir [IDV]), clinically significant relationships between sex differences in plasma drug concentrations and clinical outcomes have been observed. There appears to be a trend toward higher drug exposure in women than in men when PIs are boosted with ritonavir (RTV). Nelfinavir, the only PI that is currently administered unboosted with RTV, does not exhibit a sex difference in its plasma concentrations. Unboosted amprenavir exposure was lower in women compared with men. Sex differences in the pharmacokinetics of SQV and IDV were observed only in the setting of RTV boosting. CONCLUSIONS A common weakness in many studies addressing sex-based differences in the pharmacokinetics of antiretroviral drugs is the relatively small number of women participating. Many of these studies were retrospective in design, and some had limited pharmacokinetic parameters for comparison. Antiretroviral treatment trials should be designed with sufficient power (adequate female participation) to detect sex-based differences both in pharmacokinetics and in clinical response. Future studies should explore the molecular basis for sex-based differences in plasma drug concentrations and antiretroviral drug response. The roles of drug transporter proteins and cellular kinases, and the activities of metabolizing enzymes in mediating differential plasma and intracellular antiretroviral concentrations, should be further assessed.

HIV: Inflammation and Bone

HIV infection and antiretroviral therapy (ART) are now established independent risk factors for osteoporosis. With a spate of recent studies reporting significant elevations in fracture prevalence in HIV patients, and a rapidly aging demographic, defining the mechanisms underlying HIV/ART-induced skeletal decline has become imperative. The recent emergence of the field of “osteoimmunology” has provided a conceptual framework to explain how the immune and skeletal systems interact. Furthermore, it is becoming clear that inflammatory states leading to perturbations in the immuno-skeletal interface, a convergence of common cells and cytokine mediators that regulate both immune and skeletal systems, conspire to imbalance bone turnover and induce osteoporosis. In this review we examine the role of inflammation in the bone loss associated with diverse inflammatory conditions and new concepts into how the underlying mechanisms by which inflammation and immune dysregulation impact bone turnover may be pertinent to the mechanisms involved in HIV/ART-induced bone loss.

HIV-1 infection and antiretroviral therapies: risk factors for osteoporosis and bone fracture

Purpose of reviewPatients with HIV-1 infection/AIDS are living longer due to the success of highly active antiretroviral therapy (HAART). However, serious metabolic complications including bone loss and fractures are becoming common. Understanding the root causes of bone loss and its potential implications for aging AIDS patients will be critical to the design of effective interventions to stem a tidal wave of fractures in a population chronically exposed to HAART. Recent findingsParadoxically, bone loss may occur not only due to HIV/AIDS but also as a consequence of HAART. The cause and mechanisms driving these distinct forms of bone loss, however, are complex and controversial. This review examines our current understanding of the underlying causes of HIV-1 and HAART-associated bone loss, and recent findings pertaining to the relevance of the immuno-skeletal interface in this process. SummaryIt is projected that by 2015 more than half of the HIV/AIDS population in the USA will be over the age of 50 and the synergy between HIV and/or HAART-related bone loss with age-associated bone loss could lead to a significant health threat. Aggressive antiresorptive therapy may be warranted in high-risk patients.

Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection

Objective:Antiretroviral therapy (ART) paradoxically intensifies bone loss in the setting of HIV infection. Although the extent of bone loss varies, it occurs with virtually all ART types, suggesting a common pathway that may be aligned with HIV disease reversal. Using an animal model of immunodeficiency we recently demonstrated that immune activation associated with CD4+ T-cell reconstitution induces increased production of the osteoclastogenic cytokines RANKL and TNF&agr; by immune cells, driving enhanced bone resorption and loss in bone mineral density. Design:To confirm these findings in humans, we investigated the early kinetics of CD4+ T-cell recovery in relation to biomarkers of bone turnover and osteoclastogenic regulators in a prospective 24-week cohort study. Methods:Clinical data and blood sampling for HIV-RNA PCR, CD4+ T-cell counts, bone turnover biomarkers, and osteoclastogenic regulators were obtained from ART-naïve HIV-infected study participants initiating standard doses of lopinavir/ritonavir plus tenofovir disoproxil fumarate/emtricitabine at baseline and at weeks 2, 8, 12, and 24 post ART. Results:C-terminal telopeptide of collagen (CTx) a sensitive biomarker of bone resorption rose by 200% above baseline at week 12, remaining elevated through week 24 (&agr;<0.01), and was associated with significant increases in plasma levels of osteoclastogenic regulators [receptor activator of NF-kB ligand (RANKL), tumor necrosis factor alpha, (TNF&agr;)]. Importantly, the magnitude of CD4+ T-cell recovery correlated significantly with CTx (rs = 0.387, &agr;=0.01). Conclusion:Our data suggest that ART-induced bone loss occurs early, is aligned with early events of immune reconstitution, and these immune changes provide a unifying mechanism to explain in part the skeletal decline common to all ART.

Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss

HIV infection causes bone loss. We previously reported that immunosuppression-mediated B-cell production of receptor activator of NF-κB ligand (RANKL) coupled with decline in osteoprotegerin correlate with decreased bone mineral density (BMD) in untreated HIV-infection. Paradoxically, antiretroviral therapy (ART) worsens bone loss although existing data suggest that such loss is largely independent of specific antiretroviral regimen. This led us to hypothesize that skeletal deterioration following HIV disease reversal with ART may be related to T-cell repopulation and/or immune-reconstitution. Here we transplant T cells into immunocompromised mice to mimic ART-induced T-cell expansion. T-cell reconstitution elicits RANKL and TNFα production by B-cells and/or T-cells, accompanied by enhanced bone resorption and BMD loss. Reconstitution of TNFα- or RANKL-null T-cells and pharmacological TNFα antagonist all protect cortical, but not trabecular bone, revealing complex effects of T-cell-reconstitution on bone turnover. These findings suggest T-cell repopulation and/or immune-reconstitution as putative mechanisms for bone loss following ART initiation.

Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257

BACKGROUND Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24). METHODS Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression. RESULTS Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). CONCLUSIONS Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. CLINICAL TRIALS REGISTRATION NCT 00811954.

Liver Enzymes Elevation and Immune Reconstitution Among Treatment-Naïve HIV-Infected Patients Instituting Antiretroviral Therapy

Objectives:Because liver enzymes elevation (LEE) complicates antiretroviral (ARV) therapy, and because the strongest risk factor for ARV-related LEE is HBV/HCV coinfection, it is speculated that ARV-related LEE may be a form of immune reconstitution disease. This study summarizes the relation between immune reconstitution, ARV-induced LEE, and HBV/HCV coinfection. Methods:Medical records of ARV-naïve HIV-infected patients initiating ARV were reviewed for hepatitis coinfection, LEE (grade ≥2 AST/ALT) and changes in CD4 T-cell counts over time in an urban HIV clinic. Risk factors for LEE were statistically evaluated, and changes in CD4 T-cell counts were estimated by a mixed-effects linear model. Results:Predictors of LEE included HBV/HCV coinfection (OR = 6.44) and stavudine use (OR = 2.33). Nelfinavir use was protective (OR = 0.45). The mean rate of change in CD4 T-cell counts was higher in HBV/HCV coinfected subjects who developed LEE (99 cells/&mgr;L per month) compared with non-coinfected subjects who did not develop LEE (59 cells/&mgr;L per month, P = 0.03), non-coinfected subjects who developed LEE (36 cells/&mgr;L per month, P =0.01), and coinfected subjects who did not develop LEE, 38% higher (62 cells/&mgr;L per month; P =0.11) Conclusions:A more robust immune restoration was observed among HBV/HCV coinfected subjects who developed liver enzyme elevation after antiretroviral initiation compared with other groups. This finding suggests that ARV-related liver enzyme elevation may be related in part to immune reconstitution, as measured by changes in CD4 T-cell counts.

Physiological and pathophysiological bone turnover — role of the immune system

Osteoporosis develops when the rate of osteoclastic bone breakdown (resorption) exceeds that of osteoblastic bone formation, which leads to loss of BMD and deterioration of bone structure and strength. Osteoporosis increases the risk of fragility fractures, a cause of substantial morbidity and mortality, especially in elderly patients. This imbalance between bone formation and bone resorption is brought about by natural ageing processes, but is frequently exacerbated by a number of pathological conditions. Of importance to the aetiology of osteoporosis are findings over the past two decades attesting to a deep integration of the skeletal system with the immune system (the immuno–skeletal interface (ISI)). Although protective of the skeleton under physiological conditions, the ISI might contribute to bone destruction in a growing number of pathophysiological states. Although numerous research groups have investigated how the immune system affects basal and pathological osteoclastic bone resorption, recent findings suggest that the reach of the adaptive immune response extends to the regulation of osteoblastic bone formation. This Review examines the evolution of the field of osteoimmunology and how advances in our understanding of the ISI might lead to novel approaches to prevent and treat bone loss, and avert fractures.