Current HIV Research - Volume 8, Issue 7, 2010

Purpose of Review: Highly active antiretroviral therapy (HAART) has had an unequivocally positive impact on morbidity and mortality in HIV-infected individuals. These benefits have clearly extended to some HIV-related malignancies, including Kaposi's sarcoma and non-Hodgkin's lymphoma. The impact of HAART on cervical cancer, however, remains uncertain. The objective of this review is to summarize the last ten years of registry-based and clinical research into the impact of HAART on human papillomavirus (HPV) related cervical disease. Relevant Findings: Compared to their HIV-uninfected counterparts, HIV-infected women have an increased prevalence of HPV infection, increased risk of progression of HPV-related cervical disease, and an increased risk of invasive cervical cancer. While the partial immune reconstitution afforded by HAART might be expected to decrease susceptibility to HPV infection and cervical disease, the local effects of improved immunosurveillance on the cervix are uncertain and the increased longevity of patients on HAART may increase risk of exposure to HPV and provide the time required for progression of cervical disease. Registry-based evidence has been consistent in identifying the lack of decrease in cervical cancer incidence in the HAART era. Clinical research on the subject, however, has produced conflicting evidence with regards to both the effect of HAART on HPV infection and its impact on cervical disease progression/regression. Summary: The incidence of cervical cancer has not decreased in the HAART-era. Furthermore, clinical research has not shown a clear benefit of HAART in decreasing HPV-related cervical disease in HIV-infected women. A better understanding of this subject will have an impact on cervical disease surveillance practices.

HIV-infected infants may have CXCR4-using (X4-tropic) HIV, CCR5-using (R5-tropic) HIV, or a mixture of R5-tropic and X4-tropic HIV (dual/mixed, DM HIV). The level of infectivity for R5 virus (R5-RLU) varies among HIVinfected infants. HIV tropism and R5-RLU were measured in samples from HIV-infected Ugandan infants using a commercial assay. DM HIV was detected in 7/72 (9.7%) infants at the time of HIV diagnosis (birth or 6-8 weeks of age, 4/15 (26.7%) with subtype D, 3/57 (5.3 %) with other subtypes, P=0.013). A transition from R5-tropic to DM HIV was observed in only two (6.7%) of 30 infants over 6-12 months. Six (85.7%) of seven infants with DM HIV died, compared to 21/67 (31.3%) infants with R5-tropic HIV (p=0.09). Higher R5-RLU at 6-8 weeks was not associated with decreased survival. Infants with in utero infection had a higher median R5-RLU than infants who were HIV-uninfected at birth (p=0.025).

Objectives: We aimed at determining the incidence and factors for tenofovir disoproxil fumarate (TDF)- associated renal function decline among Thai HIV-infected patients. Methods: Retrospective and prospective cohort studies were conducted. We enrolled HIV-infected adults who had initiated TDF. Renal function decline was defined by a decrease of 25% in glomerular filtration rate (GFR) from the baseline. Factors associated with the renal function decline were determined. Results: A total of 405 patients with a median (interquartile range, IQR) body weight of 56.5 (50.5-65.0) kg were enrolled. All but four (99%) were antiretroviral treatment-experience patients. A median (IQR) duration of receiving TDF was 16 (8-21) months. Of these, 78 (19.3%) patients had a 25% decrease in GFR with the incidence rate of 16.2 per 100 person- years. By Kaplan-Meier survival analysis, median time to a 25% decrease in GFR was 28 [95% confidence interval (CI) 25.2-30.8] months. By multiple logistic regression, lower body weight [odds ratio (OR) 1.15 per 5 kg, 95% CI 1.00-1.33], lower body mass index (BMI) (OR 2.26 per 1 kg/m2, 95% CI 1.74-2.94), baseline GFR (OR 1.62 per 10 ml/min/1.73m2, 95% CI 1.39-1.88), protease inhibitor (OR 2.12, 95% CI 1.15-3.92), and nephrotoxic drug (OR 3.16, 95% CI 1.44-6.98) were statistically significant factors associated with a 25% decrease in GFR. Conclusions: The study revealed high incidence of TDF-associated renal function decline among patients with low-body weight and BMI. Additional risk factors were baseline GFR, receiving protease inhibitor, and nephrotoxic drugs. Close monitoring of renal function is warranted among patients with these risk factors.

Objectives: To estimate HIV-1 incidence and cofactors for HIV-1 incidence during pregnancy and postpartum. Design: Retrospective study among women who were HIV seronegative during pregnancy. Methods: Mothers accompanying their infants for routine 6-week immunizations at 6 maternal child health clinics in Nairobi and Western Kenya were tested for HIV-1 after completing a questionnaire that included assessment of sociodemographics, obstetric history and HIV-1 risk perception. Results: Of 2,135 mothers who had tested HIV-1 seronegative antenatally, 2,035 (95.3%) accepted HIV-1 re-testing at 6 weeks postpartum. Of these, 53 (2.6%) were HIV-1 seropositive yielding an estimated HIV-1 incidence of 6.8 (95% CI: 5.1-8.8) per 100 woman-years). Mothers who seroconverted were more likely to be employed (45.3% vs 29.0%, p=0.01), married (96.2 vs 86.6%, p=0.04) and from a higher HIV-1 prevalence region (60.4% in Western Kenya vs 28.8% in Nairobi, p<0.001). Among married women, those in polygamous relationship were significantly more likely to seroconvert (19.6% vs 6.7%, p<0.001). In multivariate analysis, region and employment independently predicted seroconversion. Conclusions: Repeat HIV-1 testing in early postpartum was highly acceptable and resulted in detection of substantial HIV-1 incidence during pregnancy and postpartum period. Within prevention of mother-to-child HIV-1 transmission programs strategic approaches to prevent maternal HIV-1 acquisition during pregnancy are urgently needed.

While significant progress has been made since 2003 when a comprehensive treatment, prevention and control program was implemented to combat the HIV/AIDS epidemic in China, new challenges are emerging. There have been limited direct case reports on profiles of HIV/AIDS patients under care at unique clinical settings in China despite significant differences between clinics in this part of the world and those in Western countries. In this report, characteristics of HIV/AIDS patients managed during a 12-month period from June 2007 to May 2008 at a major medical school-affiliated AIDS clinic in the center of Beijing are described. Our data confirm an alarming trend of increased rates of sexual transmission of HIV-1 in recent years and suggest that major improvements are needed for both the type of antiviral treatments being used and post-treatment monitoring of viral load. This information will be useful for the continued progress in the clinical management of HIV/AIDS patients in China.

Objective: Currently, 12% of the Spanish population is foreign-born, and a third of newly diagnosed HIV- infected patients are immigrants. We determined whether being an immigrant was associated with a poorer response to antiretroviral treatment. Methods: Historical multicenter cohort study of naive patients starting HAART. The primary endpoint was time to treatment failure (TTF) defined as virological failure (VF), death, opportunistic disease, treatment discontinuation (D/C), or missing patient. Secondary endpoints were TTF expressed as observed data (TFO; censoring missing patients) and time to virological failure (TVF; censoring missing patients and D/C not due to VF). A multivariate analysis was performed to control for confounders. Results: A total of 1090 treatment-naive HIV-infected patients (387 immigrants and 703 autochthonous) from 33 hospitals were included. Most immigrants were from Sub-Saharan Africa (28.3%) or South-Central America/Caribbean (31%). Immigrants were significantly younger (34 y vs 39 y), more frequently female (37.5% vs 24.6%), with less HCV coinfection than autochthonous patients (7% vs 31.3%). There were no differences in baseline viral load (4.95 Log10 vs 4.98 Log10), CD4 lymphocyte count (193.5/μL vs 201.5/μL), late initiation of HAART (56.4% vs 56.0%), or antiretrovirals used. Cox-regression analysis (HR; 95%CI) did not show differences in TTF (0.89; 0.66-1.20), TFO (0.95; 0.66-1.36), or TVF (1.00; 0.57-1.78) between immigrants and autochthonous patients. Losses to follow-up were more frequent among immigrants (17.8% vs 12.1; p=0.009). Sub-Saharan African patients and immigrant females had a significantly shorter TTF. Conclusions: The response to HAART among immigrant patients was similar to that of autochthonous patients, although they had a higher rate of losses to follow-up. Sub-Saharan Africans and immigrant females may need particular measures to avoid barriers hindering antiviral efficacy.

Acquired immunodeficiency syndrome (AIDS) is one of the most important public health problems, affecting many people every day. This syndrome is caused by the human immunodeficiency virus (HIV) and the HIV-1 protease plays an essential role by promoting virus maturation and thus infecting new cells. The HIV-1 protease is one of the main targets for anti-HIV drug therapy. The present work is a literature survey of plant extracts whose activity has been studied on HIV-1 protease. Here we list 275 species of medicinal plants, distributed in 99 families, with their place of origin, part used, type of extract, concentration and activity. We aim with this work to provide data that could be used in the research and development of new therapeutic agents for AIDS treatment.

In the present study, a comparative assessment of the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r; 4:1) on human adipocytes in culture has been performed. Human pre-adipocytes were treated with EFV or LPV/r during or after adipogenic differentiation. Acquisition of adipocyte morphology, expression of gene markers of mitochondrial toxicity, adipogenesis and inflammation, and release of adipokines and cytokines to the medium were measured. Results indicated that EFV and LPV/r impaired adipocyte differentiation in association with a reduction in transcript levels for adipogenic differentiation genes (adiponectin, lipoprotein lipase, leptin) and master regulators of adipogenesis (PPARγ, C/EBPα). The effects were greater with EFV than LPV/r. Both LPV/r and EFV induced increases in monocytechemoattractant protein-1 (MCP-1) mRNA levels, but the effect was greater with EFV. Similarly, the release of proinflammatory cytokines and other inflammation-related molecules (interleukins 6 and 8, MCP-1, PAI-1) was enhanced to a much higher degree by EFV than by LPV/r. Adiponectin and leptin release by adipocytes was reduced by both drugs, although to a higher extent by EFV. Neither drug affected mitochondrial DNA levels, transcripts encoding mitochondrial proteins or lactate release by adipocytes. In previously differentiated adipocytes, EFV caused a significant reduction in PPARγ and adiponectin expression, whereas LPV/r did not. We conclude that both EFV and LPV/r impair human adipogenesis, reduce adipokine release and increase the expression and release of inflammation-related cytokines, but the overall effects are greater with EFV. These findings may have implications for the pathogenesis of HIV-1-associated lipodystrophy and the development of HIV-1 therapies.

The cytidine deaminase APOBEC3G has been identified as an antiviral host factor that combats HIV-1. The protein was found to be present in HIV-1 target cells such as macrophages and dendritic cells. The antiviral state of these cells has been partially attributed to a G→A hypermutation of the HIV genome caused by APOBEC3G during reverse transcription. However, the viral infectivity factor (Vif) counteracts this antiviral mechanism by inducing the inactivation of APOBEC3G. In this study, we tested the effect of APOBEC3G expression on the HIV-1 infection of cells derived from purified CD34+ cells that have been transduced with lentiviral vectors containing APOBEC3G and/or shRNAs directed against APOBEC3G and then have been differentiated before infection with HIV-1. In cell lines, the infection was strongly inhibited after upregulation of APOBEC3G. The infection could then be rescued after transducing these cells with shRNAs targeting APOBEC3G. In cells derived from purified CD34+ cells a strong inhibition of the HIV-1 infection was observed in both a Vif defective HIV-1 virus and the corresponding wild-type HIV-1 virus with Vif. Our data implies that when APOBEC3G is expressed high enough, it can escape the inhibition from Vif, thereby exerting its antiviral activity.

Current HIV treatment guidelines emphasize the importance of using an active antiretroviral therapy regimen that produces full virologic suppression and immunologic competence, while at the same time providing patients with a favorable safety profile and limited risk for development of drug resistance. Etravirine (TMC125), a recently approved, non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown durable, superior virologic efficacy over placebo in the Phase III, randomized, double-blind DUET trials in 1,203 treatment-experienced, NNRTI-resistant, HIV-1-infected patients. Statistical significance of responses with etravirine over placebo was maintained through Week 24, 48 and 96, regardless of baseline demographics, baseline disease characteristics or the background regimen used. Etravirine has demonstrated a favorable safety and tolerability profile; the incidence of treatment-emergent adverse events was comparable with placebo in the DUET trials, with the exception of rash. The tolerability profile of etravirine also appears to be favorable in terms of neuropsychiatric and hepatic side effects. The pharmacokinetic profile of twice-daily etravirine minimizes the potential for clinically relevant drug-drug interactions and allows for its use in combination with a wide range of other agents. In addition, etravirine has a high genetic barrier to the development of resistance, further enhancing potential benefit in patients infected with NNRTI-resistant virus. The clinical efficacy and favorable safety profile of etravirine, together with its pharmacokinetic profile and high genetic barrier to resistance, make it a valuable treatment option for a wide range of treatment-experienced HIV-1-infected patients.