Specific sequences commonly found in the V3 domain of HIV-1 subtype C isolates affect the overall conformation of native Env and induce a neutralization-resistant phenotype independent of V1/V2 masking.

Primary HIV-1 isolates are relatively resistant to neutralization by antibodies commonly induced after infection or vaccination. This is generally attributed to masking of sensitive epitopes by the V1/V2 domain and/or glycans situated at various positions in Env. Here we identified a novel masking effect mediated by subtype C-specific V3 sequences that contributes to the V1/V2-independent and glycan-independent neutralization resistance of chimeric and primary Envs to antibodies directed against multiple neutralization domains. Positions at several conserved charged and hydrophobic sites in the V3 crown and stem were also shown to affect neutralization phenotype. These results indicated that substitutions typically present in subtype C and related V3 sequences influence the overall conformation of native Env in a way that occludes multiple neutralization targets located both within and outside of the V3 domain, and may reflect an alternative mechanism for neutralization resistance that is particularly active in subtype C and related isolates.

Sequential antiretroviral adherence measurement using electronic bottle cap monitors in a cohort of HIV-infected adults.

Most studies employing electronic bottle monitors to measure antiretroviral adherence are limited to 24 weeks of duration, providing a snapshot of adherence from a treatment course that may be lifelong. The stability of these measures in individual patients over time has not been previously described. We measured antiretroviral adherence using Medication Event Monitoring System (MEMS) caps in a patient cohort in 2004 and 2005 and repeated the measurement in 2008 and 2009. Forty-eight participants completed both monitoring periods. Mean adherence rates in the first and second periods were 74.2% and 68.9%, respectively. Adherence rates from the 2 periods for individual participants were highly correlated (Spearman rho = .66, P < .001).

Occurrence of selective ritonavir nonadherence and dose-staggering in recipients of boosted HIV-1 protease inhibitor therapy.

BACKGROUND: The inhibitory effect of ritonavir on hepatic cytochrome P450 enzymes is a critical factor in achieving optimal levels of co-administered "boosted" protease inhibitors (PIs). Even though nonadherence to antiretroviral medications is a common phenomenon, the prevalence of selective ritonavir nonadherence and dosestaggering (i.e., separating ritonavir and boosted PI doses in time) are unknown. METHODS: HIV-1-infected adults receiving a regimen containing ritonavir-boosted atazanavir or fosamprenavir were recruited into a prospective study of adherence and dosage timing of both agents. These parameters were measured over 24 weeks using the Medication Event Monitoring System (MEMS; Aardex, Union, California, USA). A subject was deemed to be selectively nonadherent to ritonavir if his/her adherence rate to the boosted PI exceeded that of ritonavir by >5%. Dose-staggering was defined as a temporal separation of boosted PI from its corresponding ritonavir dose of >4 hours but <12 hours. RESULTS: The final study population consisted of 36 subjects. Three subjects (8.3%) were selectively nonadherent to ritonavir, 17 (47.2%) staggered any doses of ritonavir, and 3 (8.3%) staggered more than 5% of their ritonavir doses. Two of these three were also selectively nonadherent to ritonavir. There was no evident impact of these behaviors on HIV viral load (VL); all subjects who were selectively nonadherent to or frequently staggered doses of ritonavir had VL <75 copies/mL at 24 weeks. CONCLUSIONS: Selective ritonavir nonadherence and dose-staggering occurs in a small but significant minority of boosted PI recipients.

HIV-infected patients receiving lopinavir/ritonavir-based antiretroviral therapy achieve high rates of virologic suppression despite adherence rates less than 95%.

BACKGROUND: The observation that extremely high levels of medication adherence are required to achieve complete virologic suppression is based largely on studies of treatment-experienced patients receiving HIV protease inhibitor (PI)-based therapy without ritonavir boosting. This study aims to define the level of adherence needed to achieve virologic suppression in patients receiving boosted PI-based highly active antiretroviral therapy (HAART) with lopinavir/ritonavir. METHODS: HIV-infected adults receiving a regimen containing lopinavir/ritonavir were recruited into a prospective, observational study of the relation between adherence to lopinavir/ritonavir and virologic outcomes. Adherence was measured using the Medication Event Monitoring System (MEMS; Aardex, Union City, CA). HIV-1 viral load (VL) was measured at week 24. RESULTS: The final study population contained 64 subjects. Eighty percent had AIDS, 97% received lopinavir/ritonavir before enrollment, and most had more than 7 years of HAART experience. Mean adherence overall was 73%. Eighty percent and 59% achieved a VL <400 copies/mL and a VL <75 copies/mL, respectively. Mean adherence was 75% in those achieving a VL <75 copies/mL. High rates of virologic suppression were observed in all adherence quartiles, including the lowest quartile (range of adherence: 23.5%-53.3%). CONCLUSIONS: Moderate levels of adherence can lead to virologic suppression in most patients taking lopinavir/ritonavir-based HAART.

Modified directly observed therapy (MDOT) for injection drug users with HIV disease.

Injection drug use is an important factor in the spread of HIV infection, and strategies to enhance adherence to HIV therapeutics are critically important to controlling viral transmission and improving clinical outcomes. To this end, the authors sought (1) to enhance adherence to highly active antiretroviral therapy (HAART) among methadone-maintained injection drug users (IDUs) using modified directly observed therapy (MDOT), and (2) to define interactions between methadone and HAART and the potential contribution of drug interactions to adherence and HIV outcomes in this population. Adherence was explored here through a pilot, unblinded, 24-week study in a methadone maintenance program in which simplified HAART (efavirenz and didanosine [one daily] and a second nucleoside [twice daily]) was administered 6 days/week by clinic staff to HIV-infected IDUs (n = 5) with their methadone. Evening doses of riboflavin-tagged nucleoside and one full day of medication weekly were given as take home doses. As a result of HAART administration, four of five participants with mean viral load at baseline of 10(5) copies/ml had undetectable viral load by 8 weeks of treatment (p = .043). Methadone area under the curve (AUC) decreased by 55% (p = .007) within 2 weeks of initiating this HAART regimen, and a mean methadone dose increase of 52% was required. The authors conclude that MDOT is a promising intervention for the treatment of IDUs with HIV disease, though significant drug interactions must be monitored for carefully and rapidly addressed.