Mark A. Boyd

Impact of viral hepatitis co-infection on response to antiretroviral therapy and HIV disease progression in the HIV-NAT cohort.

Objective: To examine the impact of viral hepatitis co-infection on HIV disease outcomes following commencement of combination antiretroviral therapy in a developing country setting. Methods: HIV RNA suppression, CD4 cell count recovery, and HIV disease progression were examined within a cohort of Thai HIV-infected patients enrolled in eight HIV-NAT randomized controlled trials of antiretroviral therapy (n = 692). Hepatitis B virus (HBV) and hepatitis C virus (HCV) testing was performed on stored serum. Results: Mean age was 32.3 years, 52% were male, 11% had CDC category C HIV disease at baseline, and 22% had received prior antiretroviral therapy. Prevalence of HBV, HCV and HBV/HCV co-infection was 8.7, 7.2 and 0.4%, respectively. Median HIV RNA reductions (log10 copies/ml) were approximately 1.5 for HIV, HIV-HBV, HIV-HCV subgroups from week 4 up to week 48. Mean increases in CD4 cell count were significantly lower among HIV-HBV and HIV-HCV subgroups at week 4 (HIV, 62 × 106 cells/l; HIV-HBV, 29 × 106 cells/l; HIV-HCV, 33 × 106 cells/l), however, by week 48 CD4 cell increases were similar (HIV, 115 × 106 cells/l; HIV-HBV, 113 × 106 cells/l; HIV-HCV, 97 × 106 cells/l). Cox regression analyses showed that HIV-HBV or HIV-HCV co-infection were not associated with a CD4 cell count increase of 100 × 106 cells/l over 48 weeks. Estimated progression to AIDS event or death at week 48 was 3.3% (95% confidence interval, 2.0–5.1%) for HIV, 6.7% (2.5–14.6%) for HIV-HBV, and 8.0% (2.2–20.5%) for HIV-HCV subgroups (P > 0.05). Conclusions: An early delayed CD4 count recovery among HIV/viral hepatitis co-infected patients was not sustained, and was not associated with increased HIV disease progression.

Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study.

Methods We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confi rmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of fi rst-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modifi ed intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463.BACKGROUND Uncertainty exists about the best treatment for people with HIV-1 who have virological failure with first-line combination antiretroviral therapy of a non-nucleoside analogue (NNRTI) plus two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NtRTI). We compared a second-line regimen combining two new classes of drug with a WHO-recommended regimen. METHODS We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confirmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of first-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modified intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463. FINDINGS We enrolled 558 patients, of whom 541 (271 in the control group, 270 in the raltegravir group) were included in the primary analysis. At 48 weeks, 219 (81%) patients in the control group compared with 223 (83%) in the raltegravir group met the primary endpoint (difference 1·8%, 95% CI -4·7 to 8·3), fulfilling the criterion for non-inferiority. 993 adverse events occurred in 271 participants in the control group versus 895 in 270 participants in the raltegravir group, the most common being gastrointestinal. INTERPRETATION The raltegravir regimen was no less efficacious than the standard of care and was safe and well tolerated. This simple NtRTI-free treatment strategy might extend the successful public health approach to management of HIV by providing simple, easy to administer, effective, safe, and tolerable second-line combination antiretroviral therapy. FUNDING University of New South Wales, Merck, AbbVie, the Foundation for AIDS Research.

Second-line combination antiretroviral therapy in resource-limited settings: facing the challenges through clinical research.

Combination antiretroviral therapy (ART) has dramatically altered the prognosis of individuals infected with HIV. In the past 5 years there has been a concerted effort to increase access to ART in the developing world. The evidence to date suggests that adherence to therapy and clinical outcomes in developing world programmes are at least the equal of those observed in developed countries. Although access to first-line therapy is reasonably well established, there is a substantial and unacceptable mortality rate in the first 6 months after initiation of ART, particularly in those with low CD4 cell counts and late-stage disease. Failure of first-line ART is inevitable in a proportion of patients. Access to second-line ART regimens in developing countries is problematic, mainly because of the expense of HIV protease inhibitors (PIs). Access to second-line ART may be facilitated by novel strategies using the existing recommended agents or by the use of new agents or classes. Refinement of programmes in the developing world must be underpinned by the same rigorous scientific research effort that has characterized the success of the effort in the developed world. Therefore, the funding bodies responsible for the roll-out of antiretroviral access across the globe must mandate, incorporate and fund clinical research as an intrinsic aspect of combination ART roll-out programmes.

Intensification of Antiretroviral Therapy With Raltegravir or Addition of Hyperimmune Bovine Colostrum in HIV-Infected Patients With Suboptimal CD4+ T-Cell Response: A Randomized Controlled Trial

BACKGROUND Despite virally suppressive combination antiretroviral therapy (cART), some HIV-infected patients exhibit suboptimal CD4(+) T-cell recovery. This study aimed to determine the effect of intensification of cART with raltegravir or addition of hyperimmune bovine colostrum (HIBC) on CD4(+) T-cell count in such patients. METHODS We randomized 75 patients to 4 treatment groups to receive raltegravir, HIBC, placebo, or both raltegravir and HIBC in a factorial, double-blind study. The primary endpoint was time-weighted mean change in CD4(+) T-cell count from baseline to week 24. T-cell activation (CD38(+) and HLA-DR(+)), plasma markers of microbial translocation (lipopolysaccharide, 16S rDNA), monocyte activation (soluble (s) CD14), and HIV-RNA (lowest level of detection 4 copies/mL) were monitored. Analysis was performed using linear regression methods. RESULTS Compared with placebo, the addition of neither raltegravir nor HIBC to cART for 24 weeks resulted in a significant change in CD4(+) T-cell count (mean difference, 95% confidence interval [CI]: 3.09 cells/μL, -14.27; 20.45, P = .724 and 9.43 cells/μL, -7.81; 26.68, P = .279, respectively, intention to treat). There was no significant interaction between HIBC and raltegravir (P = .275). No correlation was found between CD4(+) T-cell count and plasma lipopolysaccharide, 16S rDNA, sCD14, or HIV-RNA. CONCLUSION The determinants of poor CD4(+) T-cell recovery following cART require further investigation. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov identifier: NCT00772590, Australia New Zealand Clinical Trials Registry: ACTRN12609000575235.

Long-Term Survival in HIV Positive Patients with up to 15 Years of Antiretroviral Therapy

Background Life expectancy has increased for newly diagnosed HIV patients since the inception of combination antiretroviral treatment (cART), but there remains a need to better understand the characteristics of long-term survival in HIV-positive patients. We examined long-term survival in HIV-positive patients receiving cART in the Australian HIV Observational Database (AHOD), to describe changes in mortality compared to the general population and to develop longer-term survival models. Methods Data were examined from 2,675 HIV-positive participants in AHOD who started cART. Standardised mortality ratios (SMR) were calculated by age, sex and calendar year across prognostic characteristics using Australian Bureau of Statistics national data as reference. SMRs were examined by years of duration of cART by CD4 and similarly by viral load. Survival was analysed using Cox-proportional hazards and parametric survival models. Results The overall SMR for all-cause mortality was 3.5 (95% CI: 3.0–4.0). SMRs by CD4 count were 8.6 (95% CI: 7.2–10.2) for CD4<350 cells/µl; 2.1 (95% CI: 1.5–2.9) for CD4 = 350–499 cells/µl; and 1.5 (95% CI: 1.1–2.0) for CD4≥500 cells/µl. SMRs for patients with CD4 counts <350 cells/µL were much higher than for patients with higher CD4 counts across all durations of cART. SMRs for patients with viral loads greater than 400 copies/ml were much higher across all durations of cART. Multivariate models demonstrated improved survival associated with increased recent CD4, reduced recent viral load, younger patients, absence of HBVsAg-positive ever, year of HIV diagnosis and incidence of ADI. Parametric models showed a fairly constant mortality risk by year of cART up to 15 years of treatment. Conclusion Observed mortality remained fairly constant by duration of cART and was modelled accurately by accepted prognostic factors. These rates did not vary much by duration of treatment. Changes in mortality with age were similar to those in the Australian general population.

Lack of Enzyme‐Inducing Effect of Rifampicin on the Pharmacokinetics of Enfuvirtide

The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV‐1‐infected patients. In a single‐center, open‐label, one‐sequence crossover, clinical pharmacology study, 12 HIV‐1‐infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13 (morning dose only on days 3 and 13) and rifampicin (600 mg, once daily) from days 4 to 13. Plasma concentrations were measured for enfuvirtide and its metabolite (days 3 and 13) and rifampicin (day 13 only). The ratios of least squares means (LSM) and 90% confidence intervals for enfuvirtide and enfuvirtide metabolite pharmacokinetic parameters (AUC12h, Cmax, Ctrough) were estimated in the presence and absence of rifampicin. Treatments were compared using an analysis of variance for natural log‐transformed variables, with factors patient and treatment. Efficacy and safety were also monitored. Steady‐state rifampicin had no appreciable effect on any of the pharmacokinetic parameters assessed for either enfuvirtide or its metabolite. The ratio of LSM for AUC12h, Cmax, and Ctrough for enfuvirtide was 97.5%, 103%, and 84.9%, respectively, and 108%, 112%, and 92.9%, for the enfuvirtide metabolite. Rifampicin did not affect the t1/2 of enfuvirtide or its metabolite. There were no unexpected effects of rifampicin on the short‐term antiviral effect or safety of the administered antiretroviral treatment. The pharmacokinetics of enfuvirtide are not induced by a 10‐day pretreatment with rifampicin.

Improvements in antiretroviral therapy outcomes over calendar time.

Purpose of reviewThe introduction of combination antiretroviral therapy (cART) led to substantial reductions in HIV-associated morbidity and mortality. However, the regimens in the early cART era were cumbersome and toxic. The introduction of new ART agents, fixed-dose combinations and novel strategies for cART delivery such as ritonavir ‘boosting’ of HIV-protease inhibitors have led to a perception of improvements in the tolerability and durability of contemporary cART regimens. It is in turn assumed that these developments have led to improved outcomes in the latter era of cART. Recent findingsBoth cohort studies and randomized clinical trials suggest improvements in cART outcomes over calendar time. Key associated factors include reduced pill burden and dosing interval and improved tolerability and reduced toxicity of newer ART. A critical appreciation of the association between ART adherence and regimen durability has been important. Cohorts in recent times have included more patients who are completely ART-naïve at therapy initiation. SummaryThe prognosis of HIV infection in developed countries is in the order of 40 years after cART initiation. An appreciation of the factors associated with long-term control of HIV viraemia is essential for the optimal management of the HIV-infected individual in contemporary practice.

Lipid profiles in HIV-infected adults receiving atazanavir and atazanavir/ritonavir: systematic review and meta-analysis of randomized controlled trials

OBJECTIVES To compare lipid profiles in HIV-infected adults receiving atazanavir-based regimens. METHODS We conducted a systematic review of randomized controlled trials (RCTs) comparing atazanavir or atazanavir/ritonavir with a comparator and evaluated lipids at 48 weeks. We searched MEDLINE, EMBASE, CENTRAL, LILACS, Current Controlled Trials, National Institutes of Health Clinical Trials Registry, trials at AIDSinfo and HIV conference proceedings to May 2009. Standardized mean difference (SMD) between study arms in change from baseline to week 48 in lipid parameters was determined weighted by study size and 95% confidence intervals (CI) were calculated. RESULTS Nine eligible RCTs were identified (n = 3346). SMDs (mmol/L) in four RCTs comparing atazanavir/ritonavir with a ritonavir-boosted protease inhibitor were: total cholesterol, -0.62 (95% CI -0.72, -0.51); low-density lipoprotein (LDL) cholesterol, -0.31 (95% CI -0.44, -0.17); high-density lipoprotein (HDL) cholesterol, -0.16 (95% CI -0.27, -0.06); non-HDL cholesterol, -0.58 (95% CI -0.69, -0.48); and triglycerides, -0.46 (95% CI -0.58, -0.34). Atazanavir compared with non-atazanavir (three RCTs) found lower total, LDL and non-HDL cholesterol, and triglycerides [SMD -0.87 mmol/L (95% CI -0.99, -0.76); -0.56 mmol/L (95% CI -0.67, -0.45); -0.88 mmol/L (95% CI -0.99, -0.76); and -0.56 mmol/L (95% CI -0.75, -0.36), respectively], but HDL cholesterol did not differ [-0.16 mmol/L (95% CI -0.49, 0.16)]. In the atazanavir/ritonavir versus atazanavir comparison (two RCTs), total [SMD 0.44 mmol/L (95% CI 0.23, 0.65)] and non-HDL cholesterol [SMD 0.44 mmol/L (95% CI 0.23, 0.65)] were higher, but HDL cholesterol, LDL cholesterol and triglycerides were not different. CONCLUSIONS At 48 weeks, plasma lipid concentrations were lower with atazanavir/ritonavir than with other ritonavir-boosted protease inhibitor regimens. Total and non-HDL cholesterol were higher with atazanavir/ritonavir than atazanavir alone.

Raltegravir non-inferior to nucleoside based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: A randomised open label study for the treatment of HIV-1 infection

Objective To determine the durability over 96 weeks of safety and efficacy of lopinavir/ritonavir (LPV/r) and raltegravir (RAL) which was demonstrated to have non-inferior efficacy relative to a regimen of LPV/r with nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) (Control) in primary analysis at 48 weeks. Design Open label, centrally randomised trial. Setting Recruitment was from 37 primary and secondary care sites from Africa, Asia, Australia, Europe and Latin America. Subjects 541 HIV-1 infected adults virologically failing first-line non-NRTI + 2N(t)RTI, with no previous exposure to protease inhibitors or integrase strand transfer inhibitors were analysed, 425 completed 96 weeks follow up on randomised therapy. Intervention Randomisation was 1:1 to Control or RAL. Main outcome measures Differences between the proportion of participants with plasma HIV-1 RNA (VL) <200 copies/mL by intention to treat were compared with a non-inferiority margin of −12%. Differences in biochemical, haematological and metabolic changes were assessed using T-tests. Results VL <200 copies/mL at 96 weeks was: RAL 80.4%, Control 76.0% (difference: 4.4 [95%CI −2.6, 11.3]) and met non-inferiority criteria. The RAL arm had a significantly higher mean change (difference Control-RAL; 95%CI) in haemoglobin (−2.9; −5.7, −1.1), total lymphocytes (−0.2; −0.3, −0.0), total cholesterol (−0.5; −0.8, −0.3), HDL cholesterol (−0.1; −0.1, −0.0) and LDL cholesterol (−0.3; −0.5, −0.2). Conclusion At 96 weeks, both RAL and Control maintained efficacy greater than 75% and continued to demonstrate similar safety profiles. These results support the use of a combination LPV/r and RAL regimen as an option following failure of 1st line NNRTI + 2N(t)RTIs. Trial Registration ClinicalTrials.gov NCT00931463

Bone mineral density in HIV participants randomized to raltegravir and lopinavir/ritonavir compared with standard second line therapy

Objective:To compare changes over 48 weeks in bone mineral density (BMD) between participants randomized to lopinavir/ritonavir (LPV/r) + raltegravir (RAL) or LPV/r + 2–3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second line therapy. Design:48-week open-label sub-study of the Second Line trial conducted in South Africa, India, Thailand, Malaysia and Argentina. Methods:Dual energy X-ray absorptiometry scans of proximal femur and lumbar spine were performed at baseline and week 48. Linear regression was used to compare means of differences between arms. McNemars test compared osteopenia and osteoporosis. Associations between percentage BMD changes and baseline variables were assessed by multivariate linear regression. Results:Two hundred and ten participants were randomized. Analyses were adjusted for sex, BMI and smoking status. Mean (95% CI) proximal femur BMD% reduced over 48 weeks by −5.2% (−6.7 to −3.8%) in the LPV/r+2-3N(t)RTIs arm and by −2.9% (−4.3 to −1.5%) in the LPV/r+RAL arm (P = 0.0001). Lumbar spine BMD reduced by −4.2% (−5.7 to −2.7%) in the LPV/r+2-3N(t)RTIs arm and by −2.0% (−3.5 to −0.6%) in the LPV/r+RAL arm (P = 0.0006). The incidence of osteopenia (7.6%) and osteoporosis (2.0%) assessed over 48 weeks were similar between arms. Reduced BMD over 48 weeks was significantly associated with longer duration of tenofovir on study [% change (SE) −1.58 (0.38) femur, −1.65 (0.38) spine, P = 0.0001] and low baseline BMI [% change (SE) 0.5 (0.13) femur, 0.17 (0.07) spine; P < 0.01]. Conclusion:An N(t)RTI-sparing antiretroviral regimen of LPV/r and raltegravir as second line therapy is associated with less bone loss than a LPV/r regimen containing N(t)RTIs.