Babafemi Taiwo

Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262).

Objective:To explore darunavir/ritonavir (DRV/r) plus raltegravir (RAL) combination therapy in antiretroviral-naive patients. Design:Phase IIb, single-arm, open-label, multicenter study. Methods:One hundred and twelve antiretroviral-naive, HIV-1-infected patients received DRV/r 800/100 mg once daily and RAL 400 mg twice daily. Primary endpoint was virologic failure by week 24. Virologic failure was defined as confirmed viral load of 1000 copies/ml or more at week 12, or an increase of more than 0.5 log10 copies/ml in viral load from week 4 to 12, or a confirmed viral load of more than 50 copies/ml at or after week 24. Protease and integrase genes were sequenced in patients experiencing virologic failure. Results:Virologic failure rate was 16% [95% confidence interval (CI) 10–24] by week 24 and 26% (95% CI 19–36) by week 48 in an intent-to-treat analysis. Viral load at virologic failure was 51–200 copies/ml in 17/28 failures. Adjusting for age and sex, virologic failure was associated with baseline viral load of more than 100 000 copies/ml [hazard ratio 3.76, 95% CI (1.52–9.31), P = 0.004] and lower CD4 cell count [0.77 per 100 cells/&mgr;l increase (95% CI 0.61–0.98), P = 0.037]. When trough RAL concentrations were included as a time-varying covariate in the analysis, virologic failure remained associated with baseline viral load more than 100 000 copies/ml [hazard ratio = 4.67 (95% CI 1.93–11.25), P < 0.001], whereas RAL level below detection limit in plasma at one or more previous visits was associated with increased hazard [hazard ratio = 3.42 (95% CI 1.41–8.26), P = 0.006]. All five participants with integrase mutations during virologic failure had baseline viral load more than 100 000 copies/ml. Conclusion:DRV/r plus RAL was effective and well tolerated in most patients, but virologic failure and integrase resistance were common, particularly in patients with baseline viral load more than 100 000 copies/ml.

Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial.

BACKGROUND Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1. METHODS Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789. FINDINGS 174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23,100 copies per mL Vacc-4x vs 71,800 copies per mL placebo; p=0·025) and week 52 (median 19,550 copies per mL vs 51,000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations. INTERPRETATION The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies. FUNDING Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.

Antiretroviral Drug Resistance in HIV-1–Infected Patients Experiencing Persistent Low-Level Viremia During First-Line Therapy

Population sequencing was performed for persons identified with persistent low-level viremia in 2 clinical trials. Persistent low-level viremia (defined as plasma HIV-1 RNA level >50 and <1000 copies/mL in at least 2 determinations over a 24-week period, after at least 24 weeks of antiretroviral therapy) was observed in 65 (5.6%) of 1158 patients at risk. New resistance mutations were detected during persistent low-level viremia in 37% of the 54 evaluable cases. The most common mutations were M184I/V (14 cases), K103N (9), and M230L (3). Detection of new mutations was associated with higher HIV-1 RNA levels during persistent low-level viremia.

Assessing the viorologic and adherence benefits of patient-selected HIV treatment partners in a resource-limited setting.

Objective:To determine the efficacy of patient-selected treatment partners on virologic and adherence outcomes during first-line antiretroviral therapy. Design:Randomized controlled trial. Setting and Analytical Approach:Between June 2006 and December 2007, 499 HIV-infected adults in Jos, Nigeria, were randomized to standard of care (SOC) or patient-selected treatment partner-assisted therapy (TPA). Each patient was followed for 48 weeks. Virologic outcomes, adherence to drug pick-up, CD4 cell counts, and mortality are reported. Results:At week 24, undetectable viral load was achieved by 61.7% of patients in the TPA arm versus 50.2% of those receiving SOC [odds ratio (OR) = 1.58, 95% CI: 1.11 to 2.26, P < 0.05]. There was no significant difference at week 48: 65.3% versus 59.4% for TPA and SOC, respectively (OR = 1.28, 95% CI: 0.89 to 1.84, P > 0.05). The TPA group had more than 3 times the odds of at least 95% drug pickup adherence through week 24 (OR = 3.06, 95% CI: 1.89 to 4.94, P < 0.01) and almost twice the odds through week 48 (OR = 1.95, 95% CI: 1.29 to 2.93, P < 0.01). At week 48, there were no significant differences in CD4 cell count increases (t = −0.09, df = 404, P > 0.05) or mortality (10.6% vs. 6.1%) between TPA vs. SOC, respectively. Residence-to-clinic distance was significantly associated with virologic and adherence outcomes. Conclusions:Use of patient-selected treatment partners was associated with improved drug pickup adherence and initial virologic success but had no durable effect on attaining undetectable viral load.

Unmet therapeutic needs in the new era of combination antiretroviral therapy for HIV-1

Significant advances in outcomes have been achieved with combination antiretroviral therapy (cART) in patients living with HIV. However, several ongoing needs remain with respect to the development of new treatments. The need for new or enhanced cART may become increasingly apparent as patients live longer with HIV and a greater proportion die from non-AIDS-related illnesses. Immunological response to cART is variable and immune failure occurs, despite virological control. Moreover, viral suppression can be incomplete due to insufficient antiviral efficacy, acquired or transmitted drug resistance, suboptimal pharmacokinetics/pharmacodynamics and lack of adherence. Chronic immune activation may continue even when viral replication is relatively restrained. Patients continue to experience cardiovascular and metabolic complications, due to disease, treatment and ageing. In addition, neurocognitive impairment and malignancy are important sources of ongoing morbidity despite cART. HIV also affects immune system senescence and bone turnover. This review discusses potential unmet needs with respect to these issues.

Accelerated aging and human immunodeficiency virus infection: emerging challenges of growing older in the era of successful antiretroviral therapy.

HIV-infected patients are living longer as a result of potent antiretroviral therapy. Immuno-inflammatory phenomena implicated in the normal aging process, including immune senescence, depreciation of the adaptive immune system, and heightened systemic inflammation are also pathophysiologic sequelae of HIV infection, suggesting HIV infection can potentiate the biological mechanisms of aging. Aging HIV-infected patients manifest many comorbidities at earlier ages, and sometimes with more aggressive phenotypes compared to seronegative counterparts. In this review, we describe relevant biologic changes shared by normal aging and HIV infection and explore the growing spectrum of clinical manifestations associated with the accelerated aging phenotype in HIV-infected individuals.

Contemporary issues on the epidemiology and antiretroviral adherence of HIV-infected adolescents in sub-Saharan Africa: A narrative review

Adolescents are a unique and sometimes neglected group in the planning of healthcare services. This is the case in many parts of sub‐Saharan Africa, where more than eight out of ten of the worlds HIV‐infected adolescents live. Although the last decade has seen a reduction in AIDS‐related mortality worldwide, largely due to improved access to effective antiretroviral therapy (ART), AIDS remains a significant contributor to adolescent mortality in sub‐Saharan Africa. Although inadequate access to ART in parts of the subcontinent may be implicated, research among youth with HIV elsewhere in the world suggests that suboptimal adherence to ART may play a significant role. In this article, we summarize the epidemiology of HIV among sub‐Saharan African adolescents and review their adherence to ART, emphasizing the unique challenges and factors associated with adherence behaviour.

Mitochondrial function, morphology and metabolic parameters improve after switching from stavudine to a tenofovir-containing regimen

OBJECTIVES HIV-associated lipoatrophy has been associated with mitochondrial dysfunction induced by nucleoside reverse transcriptase inhibitor therapy. We hypothesize that lipid profiles and markers of mitochondrial function will improve in HIV-lipoatrophic patients switched to the nucleotide analogue tenofovir. METHODS Ten patients receiving stavudine, lamivudine and lopinavir/ritonavir (Kaletra(R)) for over 6 years were switched from stavudine to tenofovir for 48 weeks. Subcutaneous fat tissue biopsies, fasting metabolic tests, HIV RNA, CD4 cell count and whole body dual energy X-ray absorptiometry (DEXA) scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) copies/cell and mitochondrial morphology were assessed in adipose tissue biopsies, mtDNA 8-oxo-deoxyguanine in peripheral blood mononuclear cells, and glutathione (GSH) and F2-isoprostane in plasma. RESULTS There was no change in limb fat mass by DEXA; however, trunk fat mass increased by 18.9% (P = 0.01). Fasting total cholesterol decreased by 33 mg/dL (P = 0.005) and serum glucose decreased by 4 mg/dL (P = 0.039). mtDNA copies/cell increased from 386 to 1537 (P < 0.001). Transmission electron microscopy showed that mitochondrial cristae were lacking or poorly defined at study entry, whereas mitochondrial inner structures were more well defined and outer membranes were intact at 48 weeks. Oxidative damage decreased in 8/10 patients, GSH increased and F2-isoprostane decreased. CONCLUSIONS The results from this study demonstrate that systemic and peripheral fat mitochondria improve in patients switched to tenofovir following long-term exposure to stavudine, while continuing protease inhibitor therapy.

Significance and Clinical Management of Persistent Low-Level Viremia and Very-Low-Level Viremia in HIV-1-Infected Patients

ABSTRACT A goal of HIV therapy is to sustain suppression of the plasma viral load below the detection limits of clinical assays. However, widely followed treatment guidelines diverge in their interpretation and recommended management of persistent viremia of low magnitude, reflecting the limited evidence base for this common clinical finding. Here, we review the incidence, risk factors, and potential consequences of low-level HIV viremia (LLV; defined in this review as a viremia level of 50 to 500 copies/ml) and very-low-level viremia (VLLV; defined as a viremia level of <50 copies/ml detected by clinical assays that have quantification cutoffs of <50 copies/ml). Using this framework, we discuss practical issues related to the diagnosis and management of patients experiencing persistent LLV and VLLV. Compared to viral suppression at <50 or 40 copies/ml, persistent LLV is associated with increased risk of antiretroviral drug resistance and overt virologic failure. Higher immune activation and HIV transmission may be additional undesirable consequences in this population. It is uncertain whether LLV of <200 copies/ml confers independent risks, as this level of viremia may reflect assay-dependent artifacts or biologically meaningful events during suppression. Resistance genotyping should be considered in patients with persistent LLV when feasible, and treatment should be modified if resistance is detected. There is a dearth of clinical evidence to guide management when genotyping is not feasible. Increased availability of genotypic assays for samples with viral loads of <400 copies/ml is needed.

Novel antiretroviral combinations in treatment-experienced patients with HIV infection: rationale and results.

Novel antiretroviral drugs offer different degrees of improvement in activity against drug-resistant HIV, short- and long-term tolerability, and dosing convenience compared with earlier drugs. Those drugs approved more recently and commonly used in treatment-experienced patients include the entry inhibitor enfuvirtide, protease inhibitors (PIs) [darunavir and tipranavir], a C-C chemokine receptor (CCR) type 5 antagonist (maraviroc), an integrase inhibitor (raltegravir) and etravirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI). Novel agents in earlier stages of development include a CCR5 monoclonal antibody (PRO 140) administered subcutaneously once weekly, once-daily integrase inhibitors (elvitegravir and S/GSK1349572), and several nucleoside (nucleotide) reverse transcriptase inhibitors and NNRTIs. Bevirimat, a maturation inhibitor, has compromised activity in the presence of relatively common Gag polymorphisms.Viral suppression is necessary to control the evolution of drug resistance, reduce chronic immune activation that probably underlies the excess morbidity and mortality in HIV-infected patients, and reduce viral transmission, including transmitted drug resistance. In general, the proportion of viraemic patients who achieve suppression increases with the number of active pharmacokinetically compatible antiretroviral drugs in the regimen. In the ANRS139-TRIO trial, 86% of highly treatment-experienced patients treated with darunavir-ritonavir, etravirine and raltegravir had HIV RNA <50 copies/mL at 48 weeks.In patients who had received at least 12 weeks of a stable regimen and had no darunavir resistance-associated mutations, once-daily darunavir boosted with ritonavir 100 mg was virologically noninferior with better lipid effects than with the twice-daily dosing, which requires a 200 mg total daily dose of ritonavir. Raltegravir plus a boosted PI is being investigated for second-line therapy in patients not responding to NNRTI-based first-line treatment in resource-limited settings (RLS). However, concerns about this potential strategy include the low barrier against resistance of raltegravir, limited penetration of some PIs into the CNS and the unknown impact of integrase polymorphisms seen more commonly in non-B subtype HIV-1.In patients who have already achieved viral suppression, novel agents may be used to simplify the dosing schedule, lower costs (such as by switching to boosted PI monotherapy), reduce adverse events or preserve antiretroviral drug options, especially since the absence of an HIV eradication strategy implies the need for life-long combination antiretroviral therapy. Switching enfuvirtide to raltegravir eliminated painful injection-site reactions without compromising virological suppression. Two studies found different virological outcomes when patients were switched from lopinavir/ritonavir to raltegravir, but there was an improvement in the lipid profile. Simplifying to darunavir-ritonavir monotherapy after suppression of plasma HIV RNA to <50 copies/mL has been found to be safe with no emergence of resistance in cases of viral rebound, but longer-term data are needed. The initial suggestion that maraviroc may possess unique CD4+ T-cell boosting effects was not confirmed in several clinical trials.Improved understanding of HIV pathogenesis has opened new frontiers for research such as identifying the sources, consequences and optimal management of residual viraemia in those with plasma HIV RNA <50 copies/mL. Globally, however, one of the most urgent priorities is providing the increasing number of treatment-experienced virologically failing patients in RLS with access to optimal treatment, including those treatments based on novel antiretroviral agents.