NRTI-sparing Regimens Research Articles

Removing inactive NRTIs in a salvage regimen is safe, maintains virological suppression and reduces treatment costs: results from the VERITAS study (TMC114HIV4054)

Background:Despite the benefit of maintaining inactive Nucleotide/side reverse transcriptase inhibitors (NRTIs) in salvage regimens, they are associated with increased toxicity and treatment costs. Current evidence suggests that NRTI-sparing regimens in patients failing ART are non-inferior to NRTI-including regimens. This study aimed to evaluate the impact of removing at least one inactive NRTI on virologic, safety, and financial outcomes.Methods:Drug-resistant, virologically suppressed patients with CD4 >250 cells/ml on a stable regimen of four or more antiretrovirals (ARVs) were enrolled in a 48-week prospective, open-label pilot trial. One inactive NRTI was removed at baseline. Patients taking over five ARVs had a second inactive NRTI removed at 24 weeks. Viral load, CD4 count, and adverse events were assessed at baseline, 24, and 48 weeks.Results:Thirty-one male patients participated. Twenty-nine (94%) patients had lamivudine (3TC) or emtricitabine (FTC) removed and four patients had an additional NRTI removed. One patient was excluded at week 26 for discontinuing an active NRTI. All patients maintained undetectable viral loads at weeks 24 (100%) and 48 [PP = 100%; Intent-to-treat (ITT) = 97%]. At 48 weeks, patients had a median gain of 20 CD4 (IQR: − 50, +133; mean +39) compared to baseline. Three patients exhibited Grade III bilirubin elevation (two Grade II and one Grade III at baseline), which returned to baseline levels. No serious adverse events were observed. Removal of one or two ARVs equated to a mean annual savings of $3319 CDN (11%) and $8630 CDN (24%), respectively.Conclusion:Removing inactive NRTIs in patients with a controlled viral load appears to be safe, maintains virological suppression, and reduces treatment costs.

Hepatic safety of RPV/FTC/TDF single tablet regimen in HIV/HCV-coinfected patients. Preliminary results of the hEPAtic Study.

IntroductionAlthough hepatotoxicity related to antiretroviral treatment (ART) has become less frequent, hepatotoxic events, such as transaminase elevations (TE), are still a matter of concern. RPV/FTC/TDF (EPA) is a new single tablet regimen which is widely used in real life practice. Clinical trials showed an adequate profile of liver safety in the sub-population of HIV/HCV-coinfected patients receiving rilpivirine. However, the number of individuals included in these analyses is low [1]. The aim of this ongoing study is to evaluate the incidence of TE and total bilirubin elevations (TBE) during the first 48 weeks of EPA-based therapy in a large population of HIV/HCV-coinfected subjects outside of clinical trials.Patients and MethodsThis is a retrospective analysis of HIV/HCV-coinfected subjects who started EPA at the infectious diseases units of 14 centres throughout Spain, included as cases. Subjects who started an ART different to EPA during the study period at the same hospitals were selected as controls. The primary outcome variables were grade 3 or 4 TE and grade 4 TBE.ResultsOf the 191 patients included, 31 (16.2%) subjects were naïve to ART. Eighty-seven individuals started EPA and the remaining ones were controls. The most common NRTI backbone among the controls was TDF/FTC [59 (56.7%) patients] followed by NRTI-sparing regimens [24 (23.1%) individuals] and ABC/3TC [17 (16.3%) subjects]. Among controls, 67 (64.4%) started a ritonavir-boosted protease inhibitor, mainly DRV/r [41 (39.4%) patients] followed by ATV/r [16 (15.4%) subjects]. EFV, ETV and RAL were started in 16 (15.4%), 12 (11.5%) and 13 (12.5%) subjects, respectively. The median (Q1–Q3) follow-up was 5.79 (3.65–8.61) months for the cases and 11.44 (5.8–12.88) months for the controls. TE was observed in two (2.3%) cases versus five (4.8%) controls (p=0.358), accounting for a density of incidence of 4.32/100 person-years versus 5.51/100 person-years [incidence rate difference (95% confidence interval): −1.88 (−9.95–6.2), p=0.354]. All TE were grade 3 and no patient discontinued ART due to TE. None of the cases developed TBE versus four (3.8%) controls, all of them receiving ATV/r.ConclusionsThe frequency of grade 3–4 TE associated with EPA in HIV/HCV-coinfected patients under real life conditions is very low. In addition, TE in HIV/HCV-coinfected patients treated with EPA are usually mild and do not lead to treatment discontinuation. TBE was not seen in patients taking EPA. All these data confirm that EPA is safe in this particular subpopulation.

Efficacy of a dual therapy based on darunavir/ritonavir and etravirine in ART-experienced patients.

IntroductionNucleoside reverse transcriptase inhibitors (NRTI)-sparing regimens have been studied in antiretroviral therapy (ART)-naïve patients but data with ART-experienced are scarce. NRTI-sparing regimens may be an option in patients with toxicities and for simplification reasons.MethodsRetrospective multicentre analysis including ART-experienced patients starting treatment with darunavir/ritonavir and etravirine (DRV/r 800 mg/100 mg QD or 600 mg/100 mg BID and ETV 400 mg QD or 200 mg BID) with at least six months of follow-up. Primary endpoint was proportion of patients with VL<50 copies/mL at 48 weeks with an ITT analysis (missing or switch equals failure). Secondary endpoints were safety, CD4 count and lipid changes over 48 weeks.ResultsSeventy-five patients were included of whom 44 (58.6%) had HIV RNA<50 copies/mL. Baseline characteristics: median age 50 years (IQR 34–65), 72% males, 93% Caucasians, 38.6% hepatitis C, and 45.4% with CDC C stage. Median HIV duration and time on ART were 20 (IQR 7–28) and 14 years (IQR 5–21) respectively. Reasons for switching were virologic failure in 27 (36%), simplification in 25 (33.3%), toxicity in 20 (26.6%) and other 3 (4.1%). Most of them received DRV/r and ETV QD. Thirty-nine patients had NNRTI resistance mutations [28 K103N (37.3%), 6 Y181I/C (8%), 3 G190A (4%)] and 29 patients had ≥1 primary PI mutations. Main analysis (ITT) showed that 67 (89.3%) had a VL undetectable at 24 weeks (95% CI 83.1–95.5) and 57 (76%) at 48 weeks (95% CI 68.4–83.6). On treatment analysis showed that 94.3% and 89% had a viral load<50 copies at 24 and 48 weeks, respectively. 11 (14.6%) patients discontinued the regimen (three virologic failures, three switching to darunavir/ritonavir monotherapy, two to salvage regimen and three due to toxicity). No significant changes in CD4+ count and lipid changes were observed at 48 weeks.ConclusionsDual therapy with Darunavir/ritonavir and etravirine is an efficacious and safety option in ART-experienced HIV patients even in patients on virologic failure.

Lopinavir/ritonavir en nuevas estrategias de tratamiento antirretroviral de inicio

According to evidence from randomized controlled trials and epidemiological data, the antiretroviral treatment (ART) of choice has consisted of the combination of 2 nucleoside analog reverse-transcriptase inhibitors (NRTI) plus 1 non-nucleoside analog reverse-transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) for more than 17 years. There are several unresolved issues, notably the toxocity associated with NRTI, especially thymidine analogs, and the possibility of cross resistance, which may affect subsequent treatment. The development of new antiretroviral drugs with simpler dosing regimens and lower toxicity has led to evaluation of innovative strategies such as dual therapy for initial ART in treatment-naive, with the aim of preventing long-term toxicity and increasing treatment adherence. Despite encouraging results, some combinations have proven unsatisfactory. The strategies with favorable results to date consist of twice-daily lopinavir/ritonavir (LPV/r)-based regimens, those in the PROGRESS (LPV/r + raltegravir) and GARDEL (LPV/r + lamivudine) trials, and the combination of darunavir and raltegravir (NEAT 001 trial), although the latter observed a higher tendency (statistically nonsignificant) to virological failure in the dual combination arm. These trials were based on the use of NRTI-sparing regimens consisting of 2–3 fully- active agents for highly-active ART in treatment-naïve HIV-positive patients. Recent studies provide evidence supporting the use of NRTI-sparing regimens in HIV-infected patients with failure to an initial NNRTI-based ART regimen. The present review will discuss only LPV/r-based innovative strategies in initial ART regimens.

Improvement of endothelial function after switching previously treated HIV-infected patients to an NRTI-sparing bitherapy with maraviroc.

IntroductionNucleoside reverse transcriptase inhibitor (NRTI) is associated with endothelial dysfunction and proinflammatory effects. Maraviroc (MVC) is an antagonist of CCR5 receptor. CCR5 is the receptor of RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), a mediator of chronic inflammation and endothelial function. Our aim was to evaluate the maintenance of viral suppression and improvement of endothelial function in virologically suppressed HIV-infected patients switched to an NRTI-sparing combined antiretroviral therapy (cART) with MVC.Materials and MethodsThis observational, non-interventional, multicenter study was performed at the Infectious Diseases Service of Santa Lucia, Morales Meseguer, Virgen de la Arrixaca and Reina Sofía University Hospital (Murcia, Spain). The selection criteria were to be asymptomatic on a regimen with undetectable viral load (<50 HIV-RNA copies/mL) for at least six months, no previous treatment with R5 antagonists, no evidence of previous protease inhibitor (PI) failure and available R5 tropism test. Twenty-one HIV-infected patients were selected after the treatment regimen was changed to Maraviroc 150 mg/once daily plus ritonavir-boosted PI therapy. Endothelial function was prospectively evaluated through flow-mediated dilatation (FMD) of the brachial artery at baseline and at weeks 24.ResultsWe included 21 patients on treatment with PI in combination with 2 NRTI. The mean cART exposition was 133±68.9 months. Fourteen (66.6%) were males, aged 49±9 years, 15 (71.4%) smokers, 4 (19.04%) family history of coronary heart disease, 1 (5.76%) type 2 diabetes and 3 (14.28%) hypertensive, mean total cholesterol was 185.5±35 mg/dL, c-LDL 100.2±37 mg/dL, tryglicerides 170.42±92.03 mg/dL, cHDL 52.6±15.5 mg/dL, CD4 779,5±383.28 cells/mL, nadir CD4 187,96±96 cells/mL. After 24 weeks of follow-up of a switch to an NRTI-sparing regimen, 95.2% of HIV-patients on viral suppressive cART maintained viral suppression and CD4+ T cell count. This cART switch improve endothelial function in patients with lower baseline FMD levels after 24 weeks (baseline FMD −1.19±4.84 % to 24 weeks FMD 11.32±7.27%; p=0.002).ConclusionsThe results of our study show that a switch to an NRTI-sparing bi-therapy with MVC improves endothelial function and maintained the immune-virologic efficacy. This regimen emphasizes the needs for further clinical studies to associate these achievements with the incidence of non-AIDS-defining illnesses.

An NRTI-Sparing Regimen for HIV-Infected, Treatment-Naive Patients?

For antiretroviral treatment–naive individuals, several regimens are recommended; all include two nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs; either tenofovir/FTC or abacavir/lamivudine). Because of tolerability and toxicity issues with NRTIs, researchers have been investigating NRTI-free regimens for initial therapy. In a randomized, open-label, noninferiority trial involving 805 treatment-naive HIV-infected individuals in 15 European countries (88% men, 82% white, 72% men who have sex with men, 4% with hepatitis C virus coinfection), researchers compared ritonavir-boosted darunavir (100/800 mg daily) plus raltegravir (400 mg twice daily) …

Maintenance of virologic efficacy and decrease in levels of β2-microglobulin, soluble CD40L and soluble CD14 after switching previously treated HIV-infected patients to an NRTI-sparing dual therapy

Novel strategies are necessary to decrease inflammatory parameters in successfully treated HIV-infected patients. Our aim was to evaluate the maintenance of viral suppression and potential changes in inflammatory, immune-activation and coagulation biomarkers in virologically suppressed HIV-infected patients switched to a nucleoside reverse transcriptase inhibitor-sparing (NRTI) and maraviroc (MVC)-containing combined antiretroviral therapy (cART). Fifty-eight HIV-infected patients were observed after their treatment regimens were changed to MVC 150mg/once daily plus ritonavir-boosted protease inhibitor therapy. Activation-, inflammation- and coagulation-associated biomarkers and mitochondrial (mt)DNA were analyzed after a median of 24weeks of follow-up. We observed that after changing to an NRTI-sparing regimen, 96.6% of HIV-patients on viral suppressive cART maintained viral suppression and their CD4+ T cell counts did not change significantly (median of 31weeks of follow-up). This cART switch reduced soluble CD40 ligand (p=0.002), beta-2 microglobulin (p=0.025), and soluble CD14 (p=0.009) in patients with higher baseline levels of these inflammation biomarkers after a median of 24weeks of follow-up. The results of our study show that changing to NRTI-sparing dual therapy decreased the levels of inflammatory biomarkers and maintained the immune-virologic efficacy. The potential benefits of this regimen warrant further investigation to uncover the association of this therapy with the potential decrease in the morbidity and mortality of HIV-infected patients from non-AIDS-defining illnesses.

Nucleoside-Sparing Antiretroviral Regimens

Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs approved for use as antiretroviral therapy in patients infected with HIV. Despite the introduction of other classes of antiretroviral drugs, they remain an important component of combination regimens as recommended by many treatment guidelines. They also continue to be used in prevention of disease from mother to child, postexposure prophylaxis, and more recently for preexposure prophylaxis. Unfortunately, the toxicities associated with this class of drugs can limit their use. Although NRTI-sparing regimens are not currently recommended for first-line therapy there is an increasing amount of data supporting their use in both treatment-naive and in treatment-experienced patients.

NRTI-sparing regimens yield higher rates of drug resistance than NRTI-based regimens for HIV-1 treatment.

To treat human immunodeficiency virus (HIV)-infected patients, international guidelines recommend the combination of two nucleos(t)ide reverse transcriptase inhibitors [N(t)RTIs] and a third agent [non-NRTI (NNRTI), boosted protease inhibitor (r/PI) or integrase inhibitor (INI)] for initial treatment. The objective of this study was to compare the selection of resistance to antiretrovirals (ARVs) for regimens containing or lacking N(t)RTIs in patients experiencing their first virological failure. Eligible patients had a first virological failure, defined as the occurrence of two consecutive HIV plasma viral loads ≥50copies/mL. Genotypic resistance testing was performed at the time of virological failure (on the second sample with detectable viral load ≥50copies/mL) in patients failing regimens of N(t)RTIs+r/PI or NNRTI or INI, r/PI+NNRTI or INI, and INI+NNRTI. Among 434 virological failures analysed, resistance testing results were available in 416 cases (95.9%). Higher rates of drug resistance were observed in patients receiving N(t)RTI-sparing regimens. When the combination of N(t)RTIs+r/PI was used, PIs protect themselves and the associated N(t)RTIs from the selection of resistance; however, this was not observed with the NNRTI+r/PI combination. The same phenomenon was observed for raltegravir: when used in combination with N(t)RTIs, INI resistance mutations were less frequently selected compared with its use in combination with PIs or NNRTIs. In conclusion, regimens of the ARV classes combined impact the frequency of resistance development. Lower resistance is observed for N(t)RTI-based regimens, with more therapeutic options for subsequent regimens after failure.

Pharmacokinetic Study of Dual Therapy With Raltegravir 400 mg Twice Daily and Darunavir/Ritonavir 800/100 mg Once Daily in HIV-1–Infected Patients

Combinations of new classes of antiretroviral drugs are attractive options to avoid toxicity associated with nucleoside reverse transcriptase inhibitors (NRTIs) and to provide a full active regimen in patients with some degree of resistance to NRTIs. However, data on the pharmacokinetic (PK) profiles of these regimens are limited. We explore the plasma PK profile of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients. This was a pilot, open-label, fixed-sequence, prospective, single-center single-arm PK study. The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations. After at least 15 days on therapy, patients were admitted for a 24-hour PK study. Laboratory tests to assess efficacy and safety were performed at all study visits. Fifteen patients were included. The geometric mean values for DRV were AUC0-24 68,730 ng·h·mL [95% confidence interval (CI): 58,970-86,480], Ctrough 1330 ng/mL (95% CI: 1110-1760; IC-50 for wild-type and resistant HIV-1 strains was 55 and 550 ng/mL, respectively), Cmax 7630 ng/mL (95% CI: 6740-9000), and t1/2 10.9 hours (95% CI: 9.20-13.99). Geometric mean values for RAL were AUC0-12 3050 ng·h·mL (95% CI: 2530-5180); Ctrough 40 ng/mL (95% CI: 30-80), Cmax 970 ng/mL (95% CI: 840-2270), t1/2 2.68 hours (95% CI: 1.97-4.40). No adverse effects including rash or laboratory test abnormalities were noted. At week 24, the HIV-1 viral load was below 37 copies/mL in all patients. Our data suggest that dual therapy with RAL 400 mg twice daily plus DRV/RTV 800/100 mg once daily had a favorable PK profile for both drugs and that short-term efficacy and tolerability of this combination were adequate.

The Use of Nucleoside Reverse Transcriptase Inhibitors Sparing Regimens in Treatment-Experienced HIV-1 Infected Patients

Despite the relative lack of data, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-sparing regimens are increasingly prescribed in clinical practice in treatment-experienced HIV-1 infected patients. We aimed to assess the frequency of NRTI-sparing regimens among these subjects, and to evaluate and compare their safety and tolerability. Patients were included if enrolled in the currently ongoing cohorts (raltegravir and darunavir) of the Surveillance Cohort Long-Term Toxicity Antiretrovirals (SCOLTA) Project. The duration of treatment with antiretroviral therapy was evaluated using the Kaplan-Meier curve and NRTI-sparing and NRTI-based regimens were compared using the log-rank test. From 2006 to 2011, 689 experienced patients were analyzed, of whom 210 (30.5%) were on NRTI-sparing regimens. Patients on NRTI-sparing regimens were older (p=0.004) and had higher median CD4+ cell counts (p=0.002) than patients on NRTI-based regimens. The most frequent combination regimens were raltegravir plus darunavir/ritonavir (n=65; 30.95%) among patients on NRTI-sparing regimen and tenofovir DF/emtricitabine plus darunavir/ritonavir in the NRTI-containing group (n=102; 21.3%). There was no difference between groups in terms of total withdrawal, treatment discontinuation was more likely due to therapeutic failure in NRTI-sparing regimen. NRTI-sparing regimens should be evaluated in a prospective randomized trial.

Systematic Review of Antiretroviral-Associated Lipodystrophy: Lipoatrophy, but Not Central Fat Gain, Is an Antiretroviral Adverse Drug Reaction

BackgroundLipoatrophy and/or central fat gain are observed frequently in patients on antiretroviral therapy (ART). Both are assumed to be antiretroviral adverse drug reactions.MethodsWe conducted a systematic review to determine whether fat loss or gain was more common in HIV-infected patients on ART than in uninfected controls; was associated with specific antiretrovirals; and would reverse after switching antiretrovirals.ResultsTwenty-seven studies met our inclusion criteria. One cohort study reported more lipoatrophy, less subcutaneous fat gain, but no difference in central fat gain in HIV-infected patients on ART than in controls. Randomised controlled trials (RCTs) showed more limb fat loss (or less fat gain) with the following regimens: stavudine (versus other nucleoside reverse transcriptase inhibitors (NRTIs)); efavirenz (versus protease inhibitors (PIs)); and NRTI-containing (versus NRTI-sparing). RCTs showed increased subcutaneous fat after switching to NRTI-sparing regimens or from stavudine/zidovudine to abacavir/tenofovir. There were no significant between-group differences in trunk and/or visceral fat gain in RCTs of various regimens, but results from efavirenz versus PI regimens were inconsistent. There was no significant between-group differences in central fat gain in RCTs switched to NRTI-sparing regimens, or from PI-containing regimens.ConclusionsThere is clear evidence of a causal relationship between NRTIs (especially thymidine analogues) and lipoatrophy, with concomitant PIs possibly having an ameliorating effect or efavirenz causing additive toxicity. By contrast, central fat gain appears to be a consequence of treating HIV infection, because it is not different from controls, is not linked to any antiretroviral class, and doesn't improve on switching.

Suboptimal Suppression with Maraviroc plus a Boosted Protease Inhibitor

A nucleoside reverse transcriptase inhibitor (NRTI) backbone remains standard in combination antiretroviral therapy, but there is ongoing interest in developing NRTI-sparing regimens to avoid the drugs' short- and long-term toxicities. In a recent multinational, open-label, manufacturer-sponsored trial, 121 treatment-naive HIV-infected individuals with confirmed CCR5-tropic virus were randomized to receive ritonavir-boosted atazanavir in combination with either tenofovir/FTC or …

Antiretroviral regimens sparing agents from the nucleoside(tide) reverse transcriptase inhibitor class: a review of the recent literature.

The nucleoside(tide) reverse transcriptase inhibitors (NRTIs) have traditionally been an important ‘back-bone’ of an antiretroviral therapy (ART) regimen. However all agents have been associated with both short- and long-term toxicity. There have also been concerns regarding the efficacy and safety of a treatment sequencing strategy in which those with past exposure and/or resistance to one or more NRTIs are re-exposed to ‘recycled’ NRTIs in subsequent ART regimens. Newer, potent and possible safer, agents from various ART classes continue to become available. There has therefore been growing interest in evaluating NRTI-sparing regimens. In this review, we examined studies of NRTI-sparing regimens in adult HIV-positive patients with varying degrees of ART experience. We found that in treatment experienced patients currently on a failing regimen with detectable viral load, there now exists a robust evidence for the use of NRTI-sparing regimens including raltegravir with a boosted-protease inhibitor with or without a third agent. In those on a virologically suppressive regimen switching to a NRTI-sparing regimen or in those ART-naïve patients initiating an NRTI-sparing regimen, evidence is sparse and largely comes from small exploratory trials or observational studies. Overall, these studies suggest that caution needs to be exercised in carefully selecting the right candidate and agents, especially in the context of a dual-therapy regimen, to minimise the risks of virological failure. There is residual toxicity conferred by the ritonavir boost in protease-inhibitor containing NRTI-sparing regimens. Fully-powered studies are needed to explore the place of N (t)RTI-sparing regimens in the sequencing of ART. Additionally research is required to explore how to minimise the adverse effects associated with ritonavir-based pharmacoenhancement.

World AIDS Day Commemoration

This Editorial is to commemorate “World AIDS Day” by increasing the awareness of AIDS, its treatment and prevention strategies. Education is the single most crucial factor that can eradicate AIDS. On the World AIDS Day, let us commit ourselves to learning and educating the world the scourge of AIDS. What is World AIDS Day? (http://www.worldaidsday.org/about-world-aids-day.php) World AIDS Day is held on 1 December each year and is an opportunity for people worldwide to unite in the fight against HIV, show their support for people living with HIV, and to commemorate people who have died. World AIDS Day was the first ever global health day and the first one was held in 1988. Between 2011-2015, World AIDS Days will have the theme of “Getting to Zero: Zero new HIV infections. Zero discrimination. Zero AIDS related deaths”. The World AIDS Campaign focuses on “Zero AIDS related deaths” signifies a push towards greater access to treatment for all; a call for governments and pharmaceutical companies to act now. It is a call to honor promises like the Abuja declaration and for African governments to at least hit targets for domestic spending on health and HIV. (http://www.who.int/campaigns/aids-day/2013/en/) Further Reading: http://en.wikipedia.org/wiki/World_AIDS_Day As a tribute on the World AIDS Day AIDS Research and Therapy is publishing five high profile review articles to show our commitment in educating the world of the leading therapeutics and prevention efforts conducted by the dedicated research community. The articles span from Molecular Biology (Wilusz) to Humanities (Ramjee and Daniels) strategies. The goal has been to increase the awareness of therapeutics and suffering of the AIDS afflicted communities in post-HAART (highly active antiretroviral therapy) era. Specifically: Dr. Wilusz presents persuasive arguments for novel potential therapeutics strategies that take into account the unique post-transcriptional events in HIV replication. For example, involvement of HIV TAT protein on highly structured 5’ end of HIV mRNAs and active repression of a promoter proximal signal for HIV polyadenylation. Hsu et al. review serious non-AIDS events (SNAEs) such as malignancies, cardiovascular, renal and hepatic, neurological and bone disorders causing morbidity and mortality in HIV-infected individuals. Since SNAEs are multifactorial, the authors have suggested several novel strategies and interventions to reduce the burden of these disorders. Similarly, the burden of metabolic complications (MC) in HAART treated individuals is high (de Paula et al.). The authors focus on the underlying mechanisms of MC highlighting pathophysiological and epidemiological aspects during HIV infection and during HAART treatment. Management of MC in HIV population is imperative. The article by Achhra and Boyds reviews the clinical trials related to sparing antiretroviral treatment of the major class of nucleoside reverse transcriptase inhibitor (NRTI). The authors described the regimens currently used in NRTI-sparing regimen, their advantages and disadvantages, and the majority of clinical trials related to them. Finally, but most importantly, sub-Saharan Africa bears the brunt of HIV infections accounting for almost two-thirds of world’s HIV infections (Ramjee and Daniels). The worst affected are younger women who have a larger prevalence of infection. Prevention strategies are crucial that take into consideration the socioeconomic and cultural aspects of women at large. It is expected that these articles, on World AIDS Day, will increase the awareness of the AIDS burden and the strategies to combat and prevent it. Let the entire world learn the implications of AIDS so that it can be eliminated in a humanitarian way. Kailash Gupta, Ph.D. Editor-in-Chief AIDS Research and Therapy

NRTI Backbone in HIV Treatment

Nucleoside reverse transcriptase inhibitors (NRTIs) remain a critical component of therapy for HIV-infected patients. The drugs are effective, relatively inexpensive and an important component of antiretroviral therapy (ART), particularly in areas where the introduction of effective therapy has been delayed. They are an essential part of initial therapy for HIV and for prevention of mother-to-child transmission; however, toxicities and resistance may limit their use. The role for pre-exposure prophylaxis (PrEP) to reduce sexual transmission of HIV is still undefined, but this use may have a significant impact on NRTI resistance worldwide, most particularly in areas where subtype C predominates. With increasing prevalence of resistant HIV, the approval of new agents that are effective against resistant virus, and those that use novel cellular targets, are essential. Large studies are now in progress examining the safety and efficacy of NRTI-sparing regimens, but results are not currently available. NRTIs may lose relevance in the not distant future unless steps are put in place to reduce the development and spread of NRTI-resistant viruses, and new NRTIs with minimal toxicity are developed that have a novel resistance profile. This article describes the principal NRTIs, their mechanism of action, and resistance and selected toxicities of the class and of the individual drugs.

Changes in Inflammation, Oxidative Stress, Mitochondrial DNA Content after Rosiglitazone in HIV Lipoatrophy

OBJECTIVE: We aim to evaluate the mechanisms of rosiglitazone-induced fat recovery in HIV+ patients with lipoatrophy on thymidine Nucleoside Reverse Transcriptase Inhibitors (NRTI) sparing regimens. METHOD: Measures of limb fat (DXA), oxidative stress (F2 isoprostanes) and inflammation [High-sensitivity C-reactive protein (hsCRP), soluble Tumor Necrosis Factor Receptors (sTNFR)-I, sTNFR-II, and interleukin (IL)-6] were performed. Gluteal fat mitochondrial DNA (mtDNA) and peroxisome proliferator-activated receptor (PPAR)-γ RNA [expressed as PPAR-γ/Glyceraldehyde 6-Phosphate Dehydrogenase (GAPDH) RNA ratio] were measured by quantitative PCR. RESULT: 71 patients on thymidine NRTI-sparing regimens were randomized to rosiglitazone vs. placebo for 48 weeks. Duration off thymidine NRTIs was similar between groups. From week 0-48, limb fat increased significantly (p=0.02) more in the rosiglitazone than in the placebo group. Within both groups, F2-isoprostanes, sTNFR-I and sTNFR-II increased significantly (p ≤ 0.003), hsCRP decreased significantly (≤ 0.02), and IL-6 did not change. No differences were seen between groups in any of the inflammation markers. Fat mtDNA (copies/cell) increased nonsignificantly: +41(p=0.08) and +29(p=0.38) within rosiglitazone and placebo group; respectively. PPAR-γ/GAPDH ratio did not change within or between groups. CONCLUSION: Limb fat improvements seen after rosiglitazone were not associated with changes in mtDNA, oxidative or inflammation markers, or PPAR-γ expression. F2 isoprostanes and some of the inflammation markers worsened over time in these subjects on stable ART, regardless of the rosiglitazone assignment. Thus, lipoatrophy can be in part overcome by a separate pathway independent of mitochondrial DNA depletion, such as PPAR-γ.

European mitochondrial DNA haplogroups and metabolic changes during antiretroviral therapy in AIDS Clinical Trials Group Study A5142*

Mitochondrial DNA (mtDNA) influences metabolic diseases and perhaps antiretroviral therapy (ART) complications. We explored associations between European mtDNA haplogroups and metabolic changes among A5142 participants. Seven hundred and fifty-seven ART-naive patients were randomized to one of three class-sparing ART regimens including efavirenz and/or lopinavir/ritonavir with or without nucleoside reverse transcriptase inhibitors (NRTIs). Nonrandomized NRTIs included stavudine, tenofovir, or zidovudine, each with lamivudine. Fasting lipid profiles and whole-body dual-energy X-ray absorptiometry (DEXA) were performed. Nine European mtDNA haplogroups were determined for 231 self-identified non-Hispanic white individuals. Metabolic changes from baseline to 96 weeks were analyzed by haplogroup. Median age was 39 years, 9% were women, and 37, 32, and 30 were randomized to NRTI-containing regimens with either efavirenz or lopinavir/ritonavir, and an NRTI-sparing regimen, respectively. Among NRTI-containing regimens, 51% included zidovudine, 28% tenofovir, and 21% stavudine. Compared with other haplogroups, mtDNA haplogroup I (N = 10) had higher baseline non-HDL cholesterol [160 mg/dl (interquartile range 137-171) vs. 120 mg/dl (104-136); P = 0.005], a decrease in non-HDL cholesterol over 96 weeks [-14% (-20 to 6) vs. +25% (8 to 51); P < 0.001], tended to have more baseline extremity fat, and had more extremity fat loss by DEXA [-13% (-13 to 12) vs. +9% (-13 to 26); P = 0.08] and lipoatrophy (50 vs. 20%; P = 0.04). Haplogroup W (N = 5; all randomized to NRTI-sparing regimens) had the greatest increase in extremity fat [+35.5% (26.8 to 54.9); P = 0.02]. Lipids and extremity fat were associated with European mtDNA haplogroups in this HIV-infected population. These preliminary results suggest that mitochondrial genomics may influence metabolic parameters before and during ART.

Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment

The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection. Open-label study in 753 subjects randomized equally to efavirenz or lopinavir/ritonavir(r) plus two nucleoside reverse-transcriptase inhibitor (NRTI) vs. the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96 weeks were lipoatrophy, defined as at least 20% loss in extremity fat, and fasting serum lipids. Lipoatrophy by dual-energy X-ray absorptiometry at week 96 occurred in 32% [95% confidence interval (CI) 25-39%] of subjects in the efavirenz plus two NRTIs arm, 17% (95% CI 12-24) in the lopinavir/r plus two NRTIs arm, and 9% (95% CI 5-14) in the NRTI-sparing arm (P < or = 0.023 for all comparisons). Varying the definition of lipoatrophy (> or =10 to > or =40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (P < 0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dl) compared with the other two arms (+32-33 mg/dl; P < 0.001). Use of lipid-lowering agents was more common (25 vs. 11-13%) in the NRTI-sparing arm. Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.

Head-to-head comparison of two first-line regimens and an nrti-sparing regimen for initial therapy of HIV-1 infection: What should we start?

Introduction: Over the past 12 years there has been signifi cant progress in the treatment of HIV-1 infection, starting with the use of potent three-drug combinations including a protease inhibitor (PI). In 1994, there were only four drugs approved by the US Food and Drug Administration, but now there are 24 approved agents in fi ve classes and four coformulations that simplify regimens. Despite this success, debate continues about the best initial regimen to start. The Department of Health and Human Services (DHHS) guidelines currently recommend two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with either a non-NRTI (NNRTI) or a ritonavir-boosted PI (bPI) [1]. In particular, efavirenz (EFV) is the preferred NNRTI and lopinavir/ritonavir (LPV/r) is one of the preferred bPIs for fi rst-line therapy. Although there are pros and cons for each type of regimen, no preference is given. Furthermore, although regimens with a dual-NRTI backbone are most often used and have been recommended by the DHHS panel, the long-term side effects of NRTIs have sparked interest in non-NRTI–containing regimens [2,3]. The DHHS guidelines do not favor either approach and only state that the choice should be individualized, most often based on side effect profi les, drug–drug interactions, simplicity, and differences in risk of development of antiretroviral resistance. Overall, there are few comparative data for NNRTIbased versus PI-based regimens and few data on NRTI-sparing regimens. AIDS Clinical Trial Group (ACTG) 5142 was designed to evaluate effi cacy of three different types of regimens, one traditional bPI-based regimen, one traditional NNRTI-based regimen, and a novel two-drug NRTI-sparing regimen. The study enrolled patients at ACTG sites from January 2003 to May 2004.