New Publications in HIV : Archive

20 April 2009

Virologic failure endpoint definition in clinical trials: is using HIV-1 RNA threshold <200 copies/ml better than <50 copies/ml? An analysis of ACTG studies.

Ribaudo H et al. CROI 2009;Abstract 580. Feb Study evaluating a virological failure (VF) definition of 50 or 200 copies/mL.

A threshold of 50 copies/mL resulted in a high rate of false-positive VF for many patients who re-suppress to <50 copies/mL without a change in ART.

Conclusion: A threshold of 200 copies/mL may be preferable to 50 copies/mL.
Link 20 April 2009

Changing mortality risk associated with CD4 cell response to antiretroviral therapy in South Africa.

Lawn SD et al. AIDS 2009;23:335–42. Jan Observational community-based study to determine the relationship between mortality risk and the CD4 cell response to ART.

High mortality in the first year of ART was related to the proportion of time with CD4 cell counts < 200 cells/μL.

Conclusions: CD4 cell counts are the variable most strongly associated with mortality risk during ART. National HIV programmes in resource-limited settings should be designed to minimize the time patients have CD4 cell counts <200 cells/μL. Link 20 April 2009

Efficacy and tolerability of initial antiretroviral therapy: a systematic review

Carr A, Amin J. AIDS 2009;23;343–53. Systematic review of initial ART studies investigating efficacy (undetectable plasma HIV viral load by intention-to-treat) and cessation for adverse events.

Seven variables were independently associated with higher treatment success: non-white race, exclusion for low haemoglobin, lower CD4 cell count, dosing relative to food, dual-nucleoside backbone, NNRTI or ritonavir-boosted PI as the third drug and shorter follow-up. Although the most common cause of treatment cessation, adverse events were reported in only half the studies.

Conclusion: Multiple reasons influence initial ART success beyond the type of third drug and should be considered when designing and comparing studies. Most studies are too short and report insufficient adverse-event data.
Link 20 April 2009

Cost-effectiveness analysis of lopinavir/ritonavir and atazanavir+ritonavir regimens in the CASTLE study.

Simpson KN et al. 2009 Feb 14. [Epub ahead of print] Cost-effectiveness and budget-impact analysis comparing LPV/r and ATV/r for ARV-naïve patients.

Use of the LPV/r regimen saved $24,518 and $36,651 at 5 and 10 years, respectively, with lifetime cost savings estimated at $38,490.

Conclusion: In the CASTLE study, an LPV/r-based regimen in ARV-naïve patients appears to be more cost-effective than an ATV/r-based regimen. The very small added CHD risk predicted by LPV/r treatment is more than offset by the substantial short- and long-term cost savings.
Link 20 April 2009

HIV RNA levels 6 months after ART initiation is a strong, independent predictor of subsequent survival in HIV-infected individuals in Sub-Saharan Africa

Marazzi M et al. CROI 2009;Abstract 597. Feb This study investigated the prognostic role of virological response to ART in patients from five DREAM-supported sites in three countries undergoing comprehensive treatment monitoring.

In a sensitivity analysis, when the multivariable model was additionally adjusted for WHO stage, HIV RNA >10,000 copies/mL remained independently predictive of death (vs <50 copies/mL, HR 3.97; 95%CI 1.75–8.00; p=0.001).

Conclusions: An HIV RNA <10,000 copies/mL level at 6 months (12–36 weeks) after ART initiation is a strong predictor of survival In a Sub-Saharan African setting.
Link 23 April 2009

High rate of early virological failure with the once-daily tenofovir/lamivudine/nevirapine combination in naive HIV-1-infected patients

Rey D et al. J Antimicrob Chemother 2009;63:380–8. • Randomized, open-label trial comparing lamivudine, tenofovirDF and nevirapine once daily with zidovudine/lamivudine and nevirapine twice daily in naive HIV-1-infected patients.
• The results showed an unexpected and high rate of early virological failures in patients treated with once-daily lamivudine, tenofovirDF and nevirapine, with a high incidence of resistance mutations to NNRTIs and K65R conferring broad cross-resistance to nucleoside analogues.
• Conclusion: once-daily combination of tenofovirDF, lamivudine and nevirapine should not be given as a first-line ARV therapy.
Link 23 April 2009

Virologic failure endpoint definition in clinical trials: is using HIV-1 RNA threshold <200 copies/ml better than <50 copies/ml? An analysis of ACTG studies.

Ribaudo H et al. CROI 2009;Abstract 580. • Study evaluating a virological failure (VF) definition of 50 or 200 copies/mL.
• A threshold of 50 copies/mL resulted in a high rate of false-positive VF for many patients who re-suppress to <50 copies/mL without a change in ART.
• Conclusion: A threshold of 200 copies/mL may be preferable to 50 copies/mL.
Link 23 April 2009

Changing mortality risk associated with CD4 cell response to antiretroviral therapy in South Africa.

Lawn SD et al. AIDS 2009;23:335–42. • Observational community-based study to determine the relationship between mortality risk and the CD4 cell response to ART.
• High mortality in the first year of ART was related to the proportion of time with CD4 cell counts < 200 cells/μL.
• Conclusions: CD4 cell counts are the variable most strongly associated with mortality risk during ART. National HIV programmes in resource-limited settings should be designed to minimize the time patients have CD4 cell counts <200 cells/μL.
Link 23 April 2009

Efficacy and tolerability of initial antiretroviral

Carr A, Amin J. AIDS 2009;23;343–53. • Systematic review of initial ART studies investigating efficacy (undetectable plasma HIV viral load by intention-to-treat) and cessation for adverse events.
• Seven variables were independently associated with higher treatment success: non-white race, exclusion for low haemoglobin, lower CD4 cell count, dosing relative to food, dual-nucleoside backbone, NNRTI or ritonavir-boosted PI as the third drug and shorter follow-up. Although the most common cause of treatment cessation, adverse events were reported in only half the studies.
• Conclusion: Multiple reasons influence initial ART success beyond the type of third drug and should be considered when designing and comparing studies. Most studies are too short and report insufficient adverse-event data.
Link 23 April 2009

Cost-effectiveness analysis of lopinavir/ritonavir and atazanavir+ritonavir regimens in the CASTLE study.

Simpson KN et al. 2009 Feb 14. [Epub ahead of print] • Cost-effectiveness and budget-impact analysis comparing LPV/r and ATV/r for ARV-naïve patients.
• Use of the LPV/r regimen saved $24,518 and $36,651 at 5 and 10 years, respectively, with lifetime cost savings estimated at $38,490.
• Conclusion: In the CASTLE study, an LPV/r-based regimen in ARV-naïve patients appears to be more cost-effective than an ATV/r-based regimen. The very small added CHD risk predicted by LPV/r treatment is more than offset by the substantial short- and long-term cost savings.
Link 23 April 2009

HIV RNA levels 6 months after ART initiation is a strong, independent predictor of subsequent survival in HIV-infected individuals in Sub-Saharan Africa

Marazzi M et al. CROI 2009;Abstract 597. • This study investigated the prognostic role of virological response to ART in patients from five DREAM-supported sites in three countries undergoing comprehensive treatment monitoring.
• In a sensitivity analysis, when the multivariable model was additionally adjusted for WHO stage, HIV RNA >10,000 copies/mL remained independently predictive of death (vs <50 copies/mL, HR 3.97; 95%CI 1.75–8.00; p=0.001).
• Conclusions: An HIV RNA <10,000 copies/mL level at 6 months (12–36 weeks) after ART initiation is a strong predictor of survival In a Sub-Saharan African setting.
Link 23 April 2009

Editorial Comment for efficacy and tolerability of initial antiretroviral therapy.

Dorfman D. AIDS 2009;23:355–6. • Systematic review of initial ART studies investigating efficacy (undetectable plasma HIV viral load by intention-to-treat) and cessation for adverse events.
• Seven variables were independently associated with higher treatment success: non-white race, exclusion for low haemoglobin, lower CD4 cell count, dosing relative to food, dual-nucleoside backbone, NNRTI or ritonavir-boosted PI as the third drug and shorter follow-up. Although the most common cause of treatment cessation, adverse events were reported in only half the studies.
• Conclusion: Multiple reasons influence initial ART success beyond the type of third drug and should be considered when designing and comparing studies. Most studies are too short and report insufficient adverse-event data.
Link 28 April 2009

Race and sex differences in antiretroviral therapy use and mortality among HIV-infected persons in care.

Lemly DC et al. J Infect Dis 2009 Feb 16. [Epub ahead of print] • This retrospective cohort study examined all-cause mortality among HIV patients in care on HAART to investigate possible race and sex differences.
• After adjustment for baseline characteristics, death was associated with a number of factors including black race (HR 1.33; p=0.04) and female sex (HR 1.53; p=0.007).
• Conclusions: Race-associated differences in mortality probably resulted from HAART use. Women had an increased mortality risk even after adjustment for HAART use.
Link 07 May 2009

National expansion of antiretroviral treatment in Thailand, 2000-2007: program scale-up and patient outcomes

Chasombat S et al. J Acquir Immune Defic Syndr 2009;50:506–12. • This paper reports the results of the national expansion of an ARV treatment programme in Thailand from 2000 to 2007.
• The initial regimen was NVP plus two NNRTIs in 92.4% of patients. Overall 1-year survival was 0.89 (95% CI: 0.88–0.89). Death was significantly associated with male sex, age >40 years, baseline CD4 count <100 cells/mm3, symptomatic HIV or AIDS, treatment at a district or community hospital and treatment initiation before 2005.
• Conclusions: National ARV treatment programmes can be scaled up rapidly with good patient outcomes. Treatment outcomes were comparable with those for smaller cohorts in other countries and survival rates have improved since 2004.
Link 14 May 2009

A Once-Daily Lopinavir/Ritonavir-Based Regimen Is Noninferior to Twice-Daily Dosing and Results in Similar Safety and Tolerability in Antiretroviral-Naive Subjects Through 48 Weeks.

Gathe J et al. J Acquir Immune Defic Syndr 2009;50:474–81. • This study compared od and bid dosing of LPV/r plus TDF and FTC od in ARV-naïve patients.
• At week 48, 77% of od vs 76% of bid patients had HIV-1 RNA <50 copies/mL (p=0.715; 95% CI: 5–8%). Response rates, discontinuation rates and adverse events were similar in both groups.
• Conclusions: The response to LPV/r od was noninferior to bid dosing with comparable efficacy and safety. No new PI resistance mutations were detected on virologic rebound.
Link 14 May 2009

Effect of HIV-1 subtype on virologic and immunologic response to starting highly active antiretroviral therapy.

Geretti AM, Harrison L, Green H et al. Clin Infect Dis 2009;48:1296–305. • This study used data from the linked UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Study databases to investigate the effect of HIV-1 subtype (B: np1550; C: np272; A: np66; circulating recombinant form AG: np57 and D: np41) on virological and immunological response in treatment-naïve patients starting HAART.
• In adjusted analyses, VL was suppressed more rapidly in patients with subtype C (HR: 1.16; 95% CI: 1.01–1.33; p=0.04) and subtype A (HR: 1.35; 95% CI: 1.04–1.74; p=0.02) relative to subtype B. CD4-cell count recovery rates were similar for all subtypes.
• Conclusions: Patients infected with prevalent non-B subtypes were as likely to achieve VL suppression as those infected with subtype B and showed comparable rates of CD4 cell count recovery.
Link 14 May 2009

Are all subtypes created equal? The effectiveness of antiretroviral therapy against non–subtype B HIV-1

Pond SLK, Smith DM. Clin Infect Dis 2009;48:1306–9. • This study used data from the linked UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Study databases to investigate the effect of HIV-1 subtype (B: np1550; C: np272; A: np66; circulating recombinant form AG: np57 and D: np41) on virological and immunological response in treatment-naïve patients starting HAART.
• In adjusted analyses, VL was suppressed more rapidly in patients with subtype C (HR: 1.16; 95% CI: 1.01–1.33; p=0.04) and subtype A (HR: 1.35; 95% CI: 1.04–1.74; p=0.02) relative to subtype B. CD4-cell count recovery rates were similar for all subtypes.
• Conclusions: Patients infected with prevalent non-B subtypes were as likely to achieve VL suppression as those infected with subtype B and showed comparable rates of CD4 cell count recovery.
Link 14 May 2009

Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival.

Kitahata MM, Gange SJ, Abraham AG et al. N Engl J Med 2009 Apr 1. [Epub ahead of print] • This study investigated the optimal time for starting ART in asymptomatic patients by conducting two parallel analyses involving 17,517 treatment-naïve patients in the US and Canada from 1996–2005. Patients were stratified by CD4-cell count (351–500 or >500 cells/mm3) at the start of ART.
• In the first analysis, which included 8,362 patients, 2,084 (25%) started therapy at a CD4-cell count of 351–500 cells/mm3 and 6,278 (75%) delayed treatment. There was an increased risk of death of 69% with delayed versus early treatment (RR: 1.69; 95% CI: 1.26–2.26; p<0.001).
• In the second analysis, which included 9,155 patients, 2,220 (24%) started treatment at a CD4-cell count of >500 cells/mm3 and 6,935 (76%) delayed treatment. There was an increased risk of death of 94% with delayed versus early treatment (RR: 1.94; 95% CI: 1.37–2.79; p<0.001).
• Conclusions: Early initiation of ART significantly improved survival compared with delayed treatment.
Link 14 May 2009

When to Start Antiretroviral Therapy — Ready When You Are?

Sax PE, Baden LR. N Engl J Med 2009 Apr 1. [Epub ahead of print] • This study investigated the optimal time for starting ART in asymptomatic patients by conducting two parallel analyses involving 17,517 treatment-naïve patients in the US and Canada from 1996–2005. Patients were stratified by CD4-cell count (351–500 or >500 cells/mm3) at the start of ART.
• In the first analysis, which included 8,362 patients, 2,084 (25%) started therapy at a CD4-cell count of 351–500 cells/mm3 and 6,278 (75%) delayed treatment. There was an increased risk of death of 69% with delayed versus early treatment (RR: 1.69; 95% CI: 1.26–2.26; p<0.001).
• In the second analysis, which included 9,155 patients, 2,220 (24%) started treatment at a CD4-cell count of >500 cells/mm3 and 6,935 (76%) delayed treatment. There was an increased risk of death of 94% with delayed versus early treatment (RR: 1.94; 95% CI: 1.37–2.79; p<0.001).
• Conclusions: Early initiation of ART significantly improved survival compared with delayed treatment.
Link 15 May 2009

The President's Emergency Plan for AIDS Relief in Africa: An Evaluation of Outcomes.

Bendavid E, Bhattacharya J. Ann Intern Med 2009 Apr 6. [Epub ahead of print] • This study investigated the effect of the President's Emergency Plan for AIDS Relief (PEPFAR), which started in 2003, on HIV-related deaths, the number of people living with HIV, and HIV prevalence in sub-Saharan Africa.
• From 2004–2007, the difference in the annual change in the number of HIV-related deaths was 10.5% lower in the focus versus control countries (p=0.001). There was no significant difference in the annual growth in the number of people living with HIV.
• Conclusion: After 4 years of PEPFAR activity, HIV-related deaths decreased in sub-Saharan African focus versus control countries but there was no difference in trends of adult prevalence.
Link 05 June 2009

Comparison of CD4 cell count, viral load, and other markers for the prediction of mortality among HIV-1-infected Kenyan pregnant women.

Brown ER, Otieno P, Mbori-Ngacha DA et al. J Infect Dis 2009;199:1292–1300 • This study investigated the usefulness of CD4-cell count, CD4-cell percentage (CD4%), HIV-1 load, total lymphocyte count (TLC), BMI and haemoglobin measured at 32 weeks’ gestation as predictors of mortality in a cohort of women in Nairobi, Kenya.
• Mortality rates at 1 and 2 years postpartum were 2.1% (95% CI: 0.7–3.4%) and 5.5% (95% CI: 3.0–8.0%), respectively. CD4-cell count and CD4% had the highest AUC value (>0.9). BMI, TLC and haemoglobin were each associated with but poorly predictive of mortality (positive predictive value <7%). The HIV-1 load did not predict mortality beyond the CD4-cell count.
• Conclusions: The CD4-cell count and CD4% measured during pregnancy were useful predictors of mortality among pregnant women. TLC, BMI, and haemoglobin had limited predictive value. The HIV-1 load did not predict mortality any better than the CD4-cell count alone.
Link 05 June 2009

Monitoring HIV treatment in resource‐limited settings: reassuring news on the usefulness of CD4+ cell counts.

Fowler MG, Owor M. J Infect Dis 2009;199:1255–7. • This study investigated the usefulness of CD4-cell count, CD4-cell percentage (CD4%), HIV-1 load, total lymphocyte count (TLC), BMI and haemoglobin measured at 32 weeks’ gestation as predictors of mortality in a cohort of women in Nairobi, Kenya.
• Mortality rates at 1 and 2 years postpartum were 2.1% (95% CI: 0.7–3.4%) and 5.5% (95% CI: 3.0–8.0%), respectively. CD4-cell count and CD4% had the highest AUC value (>0.9). BMI, TLC and haemoglobin were each associated with but poorly predictive of mortality (positive predictive value <7%). The HIV-1 load did not predict mortality beyond the CD4-cell count.
• Conclusions: The CD4-cell count and CD4% measured during pregnancy were useful predictors of mortality among pregnant women. TLC, BMI, and haemoglobin had limited predictive value. The HIV-1 load did not predict mortality any better than the CD4-cell count alone.
Link 09 June 2009

Response to zidovudine/didanosine-containing combination antiretroviral therapy among HIV-1 subtype C-infected adults in Botswana: two-year outcomes from a randomized clinical trial.

Bussmann H, Wester CW, Thomas A et al. J Acquir Immune Defic Syndr. 2009;51:37–46. • The Tshepo study compared the efficacy and tolerability of three NRTI combinations (ZDV+3TC, ZDV+ddI and d4T+3TC) and two different NNRTIs (NVP and EFV) and two different adherence strategies (the current standard of care and an ‘intensified adherence strategy).
• The ZDV+ddI arms were discontinued due to inferiority in the primary endpoint (VF with resistance).
• VF and genotypic resistance mutations occurred in 11% of patients receiving ZDV+ddI-based ART versus 2% in patients receiving either ZDV+3TC- or d4T+3TC-based ART (p=0.002).
• The median CD4-cell count increase at 1 and 2 years was 137 and 199 cells/mm3 and the percentage of patients with plasma HIV-1 RNA level ≤400 copies/mL was 92.0% and 88.8%.
• Kaplan–Meier survival estimates at 1 and 2 years were 96.6% and 95.4%. One hundred and twenty patients (18.2%) had treatment-modifying toxicities: the most common were lipodystrophy, anaemia, neutropenia, and Stevens–Johnson syndrome.
• Conclusions: The preliminary results show overall excellent efficacy and tolerability of NNRTI-based ART among HIV-1 subtype C–infected adults. However, ZDV+ddI is inferior to d4T+3TC or ZDV+3TC when used with an NNRTI for first-line ART.
Link 24 August 2009

Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance.

Marra CM, Zhao Y, Clifford DB et al. AIDS 2009;23:1359–66. • This study investigated whether ARV regimens with good CNS penetration control HIV in the CSF by measuring the concentration of HIV RNA in CSF and blood and improve cognition by measuring neuropsychological test scores (NPZ4 and NPZ8).
• ARV regimens were graded by CNS penetration effectiveness (CPE) rank (≥2 or <2).
• The odds of suppression of CSF HIV RNA were higher with a CPE rank ≥2 than <2.
• The odds of suppression of plasma HIV RNA were not associated with CPE rank.
• Patients with impaired neuropsychological performance who received regimens with a CPE rank of ≥2 had lower composite NPZ4 scores over the course of the study.
• Conclusions: ARV regimens with good CNS penetration were more effective in controlling CSF viral replication than those with poorer penetration. ARV regimens with good CNS penetration were associated with poorer neurocognitive performance.
Link 24 August 2009

Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy.

Westreich DJ, Sanne I, Maskew M et al. Clin Infect Dis 2009;48:1617–23. • This study investigated the effect of TB treatment on stavudine toxicity among patients receiving first-line ART.
• Three exposure categories were considered: ongoing TB treatment at ART initiation, concurrent initiation of TB treatment and ART and TB treatment started after ART initiation. The outcome was single-drug stavudine substitution.
• Patients with ongoing and concurrent TB treatment were at increased risk of stavudine substitution, irrespective of stavudine dosage.
• TB treatment started after ART initiation had no effect on stavudine substitution risk.
• Conclusions: The risk of stavudine substitution was increased among patients who received TB treatment and was especially elevated during the period soon after ART initiation. In settings in which alternative ARVs are available, initiation of stavudine in patients receiving TB treatment may need to be reconsidered.
Link 25 August 2009

Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations.

Van Luin M, Gras L, Richter C et al. J Acquir Immune Defic Syndr 2009 Jul 10. [Epub ahead of print] • This study investigated whether EFV dose reduction in patients with high plasma concentrations prevents toxicity-induced EFV discontinuations.
• HIV-infected patients with a high EFV plasma concentration (≥4.0 mg/L) while using EFV 600 mg once daily as part of HAART regimen were selected from the AIDS Therapy Evaluation in The Netherlands cohort study.
• Of 180 patients with high plasma EFV levels, 47 subsequently had the dose reduced from 600 mg to 400 mg once-daily, which resulted in a 41% decrease in the median EFV plasma concentration.
• At week 48, the Kaplan-Meier estimated cumulative incidence of toxicity-induced EFV discontinuations was 11.5% in patients on the standard dose versus 2.3% in patients who had a dose reduction (p=0.066, log-rank test).
• Dose reduction was not associated with loss of virological suppression.
• Conclusions: Dose reduction may prevent toxicity-induced discontinuations in patients with high EFV plasma concentrations without compromising virological efficacy.
Link 16 September 2009

Rate of accumulation of thymidine analogue mutations in patients continuing to receive virologically failing regimens containing zidovudine or stavudine: implications for antiretroviral therapy programs in resource-limited settings.

Cozzi-Lepri A, Phillips AN, Martinez-Picado J et al. J Infect Dis 2009;200:687–97. • This study investigated the effect of continuing virologically failing ART in resource-limited settings in terms of the rate of accumulation of thymidine analogue mutations (TAMs).
• The study included patients in EuroSIDA with two genotypic resistance tests ([HIV RNA >500 copies/mL in any measure between tests, the first being performed after the first VF of a TA, which was continued until the second test.
• At the first test, 1 year after VF, a median of three TAMs were detected. Overall, 126 TAMs were accumulated during 548 person-years of follow-up (1/4.3 years; 95%CI: 3.7–5.0 years).
• Greater predicted activity of the TA at t0, TAM profile 2 (versus TAM profile 1) at t0, use of a NNRTI at t0 (versus combined NNRTI and PI), and heterosexual acquisition of HIV (versus homosexual) were associated with a faster rate of TAM accumulation.
• Conclusions: Although the estimated rate of TAM accumulation was lower than anticipated, all possible efforts should be continued to increase the availability of drug options in resource-limited settings.
Link 16 September 2009

Slow accumulation of HIV resistance mutations: implications for resource-limited settings?

Stevens WS. J Infect Dis 2009;200:670–2. • This study investigated the effect of continuing virologically failing ART in resource-limited settings in terms of the rate of accumulation of thymidine analogue mutations (TAMs).
• The study included patients in EuroSIDA with two genotypic resistance tests ([HIV RNA >500 copies/mL in any measure between tests, the first being performed after the first VF of a TA, which was continued until the second test.
• At the first test, 1 year after VF, a median of three TAMs were detected. Overall, 126 TAMs were accumulated during 548 person-years of follow-up (1/4.3 years; 95%CI: 3.7–5.0 years).
• Greater predicted activity of the TA at t0, TAM profile 2 (versus TAM profile 1) at t0, use of a NNRTI at t0 (versus combined NNRTI and PI), and heterosexual acquisition of HIV (versus homosexual) were associated with a faster rate of TAM accumulation.
• Conclusions: Although the estimated rate of TAM accumulation was lower than anticipated, all possible efforts should be continued to increase the availability of drug options in resource-limited settings.
Link 16 September 2009

Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial.

Lennox JL, Dejesus E, Lazzarin A et al. Lancet 2009 Jul 31 [Epub ahead of print] • This study compared the safety and efficacy of RAL with EFV as part of ART for treatment-naive patients.
• Patients (n=556) were randomised to 400 mg oral RAL twice daily (n=281) or 600 mg oral EFV (282) once daily, in combination with TDF and FTC. Three patients were not treated.
• The primary efficacy endpoint was a viral RNA concentration <50 copies/mL at week 48 in the per-protocol population.
• In the RAL group, 86.1% (n=241 patients) and 81.9% (n=230) in the EFV group patients achieved the primary endpoint (difference 4.2%; 95% CI: –1.9 to 10.3).
• The time to viral suppression was shorter for RAL than EFV (log-rank test p<0.0001).
• Significantly fewer drug-related adverse events occurred with RAL (n=124 [44.1%]) than EFV (n=217 [77.0%]; difference –32.8%; 95% CI: –40.2 to –25.0; p<0.0001).
• Conclusions: RAL-based ART had rapid and potent ARV activity, which was non-inferior to that of EFV at week 48. RAL is a well-tolerated alternative to EFV as part of ART in treatment-naïve patients.
Link 16 September 2009

Raltegravir: a new choice in HIV and new chances for research.

Emery S, Winston A. Lancet 2009 Jul 31 [Epub ahead of print] • This study compared the safety and efficacy of RAL with EFV as part of ART for treatment-naive patients.
• Patients (n=556) were randomised to 400 mg oral RAL twice daily (n=281) or 600 mg oral EFV (282) once daily, in combination with TDF and FTC. Three patients were not treated.
• The primary efficacy endpoint was a viral RNA concentration <50 copies/mL at week 48 in the per-protocol population.
• In the RAL group, 86.1% (n=241 patients) and 81.9% (n=230) in the EFV group patients achieved the primary endpoint (difference 4.2%; 95% CI: –1.9 to 10.3).
• The time to viral suppression was shorter for RAL than EFV (log-rank test p<0.0001).
• Significantly fewer drug-related adverse events occurred with RAL (n=124 [44.1%]) than EFV (n=217 [77.0%]; difference –32.8%; 95% CI: –40.2 to –25.0; p<0.0001).
• Conclusions: RAL-based ART had rapid and potent ARV activity, which was non-inferior to that of EFV at week 48. RAL is a well-tolerated alternative to EFV as part of ART in treatment-naïve patients.
Link 16 November 2009

High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO trial.

Yazdanpanah Y, Fagard C, Descamps D et al. Clin Infect Dis 2009;49:1441–9. • This phase II, non-comparative, multicentre study investigated the safety and efficacy of RAL plus ETV and DRV/r in treatment-experienced patients with multidrug-resistant HIV.
• The primary endpoint was the proportion of patients with plasma HIV RNA levels <50 copies/mL at 24 weeks.
• In addition to the investigational drugs, 90 patients (87%) received optimised background therapy that included NRTIs (86 patients) or ENF (12 patients).
• At weeks 24 and 48, 90% (95% CI: 85–96%) and 86% (95% CI: 80–93%) of patients, respectively, had an HIV RNA level <50 copies/mL. The median CD4 cell count increase was 108 cells/mm3.
• Grade 3/4 adverse events were reported in 15 patients (14.6%). Only one patient discontinued the investigational regimen because of an adverse event.
• Conclusions: The combination of RAL, ETV and DRV/r was well tolerated in treatment-experienced patients infected with multidrug-resistant virus and was associated with a rate of virologic suppression similar to that expected in treatment-naïve patients.
Link 16 November 2009

The risk of virologic failure decreases with duration of HIV suppression, at greater than 50% adherence to antiretroviral therapy

Rosenblum M, Deeks SG, van der Laan M et al. PLoS One 2009;4:e7196. • This study investigated the hypothesis that the percentage adherence to ART necessary to maintain HIV suppression would decrease the longer the duration of viral suppression.
• Adherence to ART was measured through pill counts. The effect of adherence to ART on the probability of VF during early and late viral suppression was determined.
• Comparing the probability of VF just after achieving viral suppression vs after 12 consecutive months of suppression, there was a statistically significant decrease in the probability of VF for each range of adherence proportions considered, as long as adherence was >50%.
• The estimated risk difference, comparing the probability of VF after 1 month vs after 12 months of continuous viral suppression was 0.47 (95% CI: 0.23–0.63) at 50–74% adherence, 0.29 (95% CI: 0.03–0.50) at 75–89% adherence and 0.36 (95% CI: 0.23–0.48) at 90–100% adherence.
• Conclusions: The risk of VF for adherence >50% declined with a longer duration of continuous viral suppression.
Link 07 December 2009

Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America.

Deeks SG et al. Clin Infect Dis 2009;49:1582–90. • This study used Multivariate Cox regression to assess the factors associated with time to second regimen failure and time to death after the onset of second regimen failure in patients who experienced VF (defined as an HIV RNA level >1000 copies/mL), received modified therapy and then had a second episode of VF.
• Of 42,790 patients who received therapy, 7,159 experienced a second VF. The risk of second VF decreased from 1996 (56 cases per 100 person-years) through 2005 (16 cases per 100 person-years; p<0.001). The cumulative mortality after onset of second VF was 26% at 5 years and decreased over time.
• A history of AIDS, a lower CD4+ T-cell count and a higher plasma HIV RNA level were each independently associated with mortality.
• Conclusions: Mortality rates for those who have experienced failure of two or more regimens have remained high. Plasma HIV RNA levels, CD4+ T-cell counts at time of treatment failure and a history of AIDS remain independent risk factors for death. These factors remain important targets for those in need of more aggressive therapeutic interventions.
Link 07 December 2009

Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial.

Jaffar S et al. Lancet. 2009 Nov 23. • This study investigated whether home-based HIV care was as effective as facility-based care.
• The primary endpoint was VF, defined as RNA >500 copies/mL after 6 months’ treatment.
• Of 729 home-care patients, 117 (16%) had VF versus 80 of 483 (17%) in facility care. VF rates per 100 person-years were 8.19 (95% CI: 6.84–9.82) for home and 8.67 (95% CI: 6.96–10.79) for facility care (rate ratio [RR] 1.04, 0.78–1.40; equivalence shown).
• Mortality rates were similar: 0.95 (0.71–1.28).
• Conclusions: Home-based HIV care was as effective as a clinic-based strategy and could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care.
Link 07 December 2009

ART in rural Uganda—efficient scale-up with home-based care?

Korenromp EL, Viisainen KM Lancet. 2009 Nov 23. • This study investigated whether home-based HIV care was as effective as facility-based care.
• The primary endpoint was VF, defined as RNA >500 copies/mL after 6 months’ treatment.
• Of 729 home-care patients, 117 (16%) had VF versus 80 of 483 (17%) in facility care. VF rates per 100 person-years were 8.19 (95% CI: 6.84–9.82) for home and 8.67 (95% CI: 6.96–10.79) for facility care (rate ratio [RR] 1.04, 0.78–1.40; equivalence shown).
• Mortality rates were similar: 0.95 (0.71–1.28).
• Conclusions: Home-based HIV care was as effective as a clinic-based strategy and could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care.
Link 02 March 2010

Nevirapine/zidovudine/lamivudine has superior immunological and virological responses not reflected in clinical outcomes in a 48-week randomized comparison with abacavir/ zidovudine/lamivudine in HIV-infected Ugandan adults with low CD4 cell counts.

Munderi P et al. HIV Med 2010 Feb 2. • This safety study compared NVP with ABC in ARV-naïve patients with CD4 cell counts <200 cells/mm3 in two Ugandan DART centres.
• Documented WHO stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses were ITT.
• The study drug was substituted in 7% of ABC patients vs 11% of NVP patients (p=0.09). At 48 weeks, 62% of ABC patients vs 77% of NVP patients had a VL <50 copies/mL (P<0.001) and mean CD4 cell count increases from baseline were +147 vs +173 cells/mm3, respectively (p=0.006).
• Twenty ABC patients vs 32 NVP patients developed new or recurrent WHO 4 events or died (HR: 0.60; 95% CI: 0.34–1.05; p=0.07) and 48 vs 68 developed new or recurrent WHO 3/4 events or died (HR: 0.67; 95% CI: 0.46–0.96; p=0.03).
• Conclusions: The clear virological/immunological superiority of NVP over ABC was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/VL to predict initial efficacy is unexplained and requires further evaluation.
Link 22 March 2010

Pretreatment CD4 cell slope and progression to AIDS or death in HIV-infected patients initiating antiretroviral therapy--the CASCADE collaboration: a collaboration of 23 cohort studies.

Wolbers M et al. PLoS Med 2010;7:e1000239. • This survival analysis of patients from 23 cohorts of the CASCADE study investigated whether the rate of CD4 cell decline prior to ART is related to prognosis and should affect when ART is started.
• A pre-ART CD4 slope was estimated using a linear mixed effects model for each patient. The primary outcome was the time from starting ART to the first new AIDS event or death.
• The HR for AIDS or death was 1.01 (95% CI: 0.97–1.04) for each 10 cells/mm3 per year reduction in pre-ART CD4 cell decline.
• There was no association between pre-ART CD4 cell slope and survival.
• Conclusions: The CD4 cell slope did not improve the prediction of clinical outcome in patients with a CD4 cell count >350 cells/mm3.
Link 22 March 2010

Virological follow-up of adult patients in antiretroviral treatment programmes in sub-Saharan Africa: a systematic review.

Barth RE et al. Lancet Infect Dis 2010;10:155–66. • This article reviews the virological efficacy and drug-resistance outcomes of 89 ART studies in sub-Saharan Africa.
• In an on-treatment analysis, 10,351 (78%) of 13,288 patients showed virological suppression after 6 months of ART, 7413 (76%) of 9,794 after 12 months and 3,840 (67%) of 5,690 after 24 months.
• Resistance profiles were associated with commonly used ARVs: the lamivudine-associated M184V mutation was most frequent, followed by the NNRTI-associated K103N mutation. Thymidine-analogue mutations and the K65R mutation were less frequent.
• Conclusions: First-line ART regimens used in sub-Saharan Africa were effective. Drug-resistance profiles suggest that a PI-based regimen with a NRTI backbone is a reasonable second-line option.
Link 25 June 2010

Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety.

Hamill RJ et al. Clin Infect Dis 2010;51:225–32. • This study compared the efficacy and safety of liposomal amphotericin B (3 or 6mg/kg/day) with that of conventional amphotericin deoxycholate in patients with AIDS and acute cryptococcal meningitis.
• Efficacy was similar for all three treatments.
• The overall incidence of infusion-related reactions was significantly lower for both liposomal doses compared with conventional amphotericin B (p<0.001).
• The 3 mg/kg/day liposomal amphotericin B dose was associated with significantly less nephrotoxicity than conventional amphotericin B (p=0.004).
• Conclusions: Liposomal amphotericin B provides an equally effective alternative to conventional amphotericin B deoxycholate in patients with AIDS and acute cryptococcal meningitis.
Link 05 July 2010

Effect of treating co-infections on HIV-1 viral load: a systematic review

Modjarrad K, Vermund SH. Lancet Infect Dis, 2010;10:455–63 • This systematic review assessed the effect of treating key co-infections on plasma HIV-1-RNA levels in resource-constrained countries.
• Standardised mean plasma VL decreased after the treatment of co-infecting pathogens in all 18 studies.
• Twelve of 14 studies with variance data reported significant differences in HIV VL before and after treatment.
• Conclusions: Although many of the VL reductions were ≤1.0 log10 copies/mL, even small changes in plasma HIV-RNA concentrations can slow HIV progression and could translate into population-level benefits in lowering the risk of HIV transmission.
Link 29 July 2010

Rate of CD4+ cell count increase over periods of viral load suppression: relationship with the number of previous virological failures.

Trotta MP et al. Clin Infect Dis 2010;51:456–64. • This study analysed patients with ≥1 episode of viral suppression after starting first-line ART (n=3,537) from the ICONA Foundation study.
• The percentage of patients with an increase in CD4 cell count >300 cells/mm3 and the rate of CD4 cell count increase per year were estimated.
• The median time to reach a CD4 cell count increase >300 cells/mm3 was significantly associated with the number of failed regimens: 34, 41, 51 and 45 months in patients without evidence of previous virological failure and 1, 2 or ≥3 previous virological failures, respectively (p<0.001). The annual estimated increases in CD4 cell count were 36, 28, 31 and 26 cells/mm3, respectively.
• Conclusions: Patients with ≥1 virological failure took a longer time to reach a CD4 cell count >300 cell/mm3 and had a slower annual increase than those without virological failure.
• First-line ART should be optimised to provide the best chance of achieving an effective CD4 cell response.
Link