Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels compared to protease inhibitor-based therapy.

Background: It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (HIV) replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Methods: CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n = 100, n = 124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART. Results: In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho = 0.70 and rho = 0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj = 0.048 and padj = 0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals. Conclusions: All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size. Funding: This work was supported by ZonMw (09120011910035) and FP7 Health (305522).

Discordant Treatment Responses to Combination Antiretroviral Therapy in Rwanda: A Prospective Cohort Study.

INTRODUCTION: Some antiretroviral therapy naïve patients starting combination antiretroviral therapy (cART) experience a limited CD4 count rise despite virological suppression, or vice versa. We assessed the prevalence and determinants of discordant treatment responses in a Rwandan cohort. METHODS: A discordant immunological cART response was defined as an increase of <100 CD4 cells/mm3 at 12 months compared to baseline despite virological suppression (viral load [VL] <40 copies/mL). A discordant virological cART response was defined as detectable VL at 12 months with an increase in CD4 count ≥100 cells/mm3. The prevalence of, and independent predictors for these two types of discordant responses were analysed in two cohorts nested in a 12-month prospective study of cART-naïve HIV patients treated at nine rural health facilities in two regions in Rwanda. RESULTS: Among 382 patients with an undetectable VL at 12 months, 112 (29%) had a CD4 rise of <100 cells/mm3. Age ≥35 years and longer travel to the clinic were independent determinants of an immunological discordant response, but sex, baseline CD4 count, body mass index and WHO HIV clinical stage were not. Among 326 patients with a CD4 rise of ≥100 cells/mm3, 56 (17%) had a detectable viral load at 12 months. Male sex was associated with a virological discordant treatment response (P = 0.05), but age, baseline CD4 count, BMI, WHO HIV clinical stage, and travel time to the clinic were not. CONCLUSIONS: Discordant treatment responses were common in cART-naïve HIV patients in Rwanda. Small CD4 increases could be misinterpreted as a (virological) treatment failure and lead to unnecessary treatment changes.

Safety of long-term interruption of successful antiretroviral therapy: the ATHENA cohort study.

We studied the dynamics of CD4 cell counts after the interruption of virologically successful highly active antiretroviral therapy (HAART) in 139 patients. Changes in CD4 cell counts during HAART interruption followed a biphasic pattern: an initial rapid decline during the first month followed by a slow decrease. During 48 weeks of follow-up mean CD4 cell counts remained just above the mean pre-HAART level. This limits the feasibility of structured treatment interruptions for patients with low nadir CD4 cell counts.

Cervical and anal HPV infection: cytological and histological abnormalities in HIV-infected women in Thailand.

BACKGROUND: Women infected with human immunodeficiency virus (HIV) have higher rates of persistent infection with high-risk human papillomavirus (hr-HPV) and cervical and anal dysplasia. We describe the epidemiology of hr-HPV, and cervical and anal intra-epithelial abnormalities in HIV-infected women in Thailand. METHODS: HIV-infected women aged 18-49 years, either HAART-naïve or -experienced, were enrolled in Bangkok, Thailand. A demographic and sexual-risk behaviour questionnaire was administered and a pelvic examination with colposcopy was performed on every woman. Cervical and anal samples were tested for cytology and HPV genotyping. RESULTS: A total of 256 women were enrolled with a median [interquartile range (IQR)] age of 35 (32-40) years. Ninety (35.2%) had detectable cervical hr-HPV. Being post-menopausal was associated with increased risk for cervical hr-HPV, while years since HIV diagnosis and plasma HIV RNA <40 copies/mL were significantly associated with decreased risk in multivariable regression analyses. Abnormal cervical cytology was detected in 6.3%. Cervical biopsies that were taken from 99 women (39.3%) owing to abnormalities seen during colposcopy showed cervical intra-epithelial neoplasia (CIN) in 22.6%. The sensitivity of cervical cytology to detect CIN2+ was 10.0%. Among 102 women enrolled in the anal substudy, 18.8% had anal HPV infection and 11.1% had anal hr-HPV. Two women had abnormal anal cytology. CONCLUSION: We found cervical and anal hr-HPV in 35.2% and 11.1% of Thai HIV-infected women, respectively. Moreover, the observed poor agreement between cervical cytology and histology results could indicate current cervical cancer screening programs for HIV-infected women might not be optimal for the detection of pre-neoplastic lesions.

When to Start Antiretroviral Therapy and What to Start With-- A European Perspective.

Although antiretroviral combination therapy has greatly improved the life expectancy of HIV-infected individuals, its use is hampered by considerable toxicity, the need for life-long near-perfect adherence to strict dosing regimens in order to avoid the emergence of drug resistance, and high cost. In this paper we review current understanding of when to best initiate antiretroviral therapy and what regimen to start with. The limitations of antiretroviral combination therapy are increasingly clear, and this has led to the current tendency to delay the initiation of therapy until CD4 cell counts have consistently dropped toward the 200 cells/mm(3 )mark, or until plasma HIV-1 RNA has increased to above 100,000 copies/mL. The need for optimal adherence also implies a "readiness" on the part of the patient to start treatment. Once the decision to commence therapy has been reached, what particular combinations of drugs to start with increasingly demands an individualized approach.