Current HIV Research (v.9, #2)

Anal Cancer: Focus on HIV-Positive Patients in the HAART Era by Ernesto Zanet, Massimiliano Berretta, Ferdinando Martellotta, Bruno Cacopardo, Rossella Fisichella, Marcello Tavio, Salvatore Berretta, Umberto Tirelli (70-81).
Anal cancer represents an increasing health problem, especially in immune-compromised patients, as HIVpositive patients. Notably, a significant higher incidence rate is reported among HIV infected patients with the advent of highly active antiretroviral therapy (HAART). To date, no randomised trial supports the correlation between existing screening strategies and reduced progression of anal intraepithelial neoplasia (AIN) to anal cancer or improved survival. Nevertheless, screening and treatment of AIN by topical agents should be implemented in high risk population. Data on invasive anal cancer treatment show that combined modality treatment (CMT) is the treatment of choice. Early reports on HIV-positive patients describe higher treatment toxicity and a relation with lower CD4 count and higher HIV viral load. More recently, reported outcomes seem to be similar in HIV-positive population and general population. Reports on a rise in local recurrence rates and in acute side effects along with a correlation with pre-treatment CD4 counts in HIV-positive patients, are not confirmed by all authors. The development of the first approved vaccine is a milestone in the field of anogenital cancers. However, many questions are still unresolved especially as concerns immunization in the setting of HIV infection.

Impact of the Frequency of Plasma HIV-1 RNA Monitoring on the Outcome of Antiretroviral Therapy by Romanee Chaiwarith, Jutarat Praparattanapan, Nontakan Nuntachit, Wilai Kotarathitithum, Thira Sirisanthana, Khuanchai Supparatpinyo (82-87).
Background: Current guidelines for HIV management recommend monitoring plasma HIV-1 RNA level every 3-6 months in patients on a stable antiretroviral regimen. However, cost is the major obstacle to follow the guidelines in resource-limited settings. Objective: This study aimed to compare the outcome of antiretroviral therapy among HIV-infected patients on a stable regimen who had plasma HIV-1 RNA monitoring once vs twice yearly. Methods: A retrospective cohort study was conducted among HIV-infected patients receiving antiretroviral therapy since 2002 at Chiang Mai University Hospital, Thailand. We evaluated the incidence of virological failure and number of reverse transcriptase (RT) mutations between groups. Results: Of 551 patients on a stable antiretroviral regimen, 405 (73.5and#x25;) and 146 (26.5and#x25;) patients had plasma HIV-1 RNA measurement once and twice yearly, respectively. Forty-seven of 405 patients (11.6and#x25;) in once-yearly group and 15 of 146 patients (10.3and#x25;) in twice-yearly group developed virological failure, giving the incidence rate of 2.03/100 and 1.95/100 person-years, respectively. The probability of virological failure did not differ between groups (p=0.897, log-rank test). The number of RT mutations was not statistically different between groups (all p-values > 0.05). The predicting factors for virological failure from a multivariate analysis were adherence rate andlt; 95and#x25;% and baseline CD4 cell count andlt; 50 cells/mm3 but not the frequency of HIV-1 RNA monitoring. Conclusions: The incidence of virological failure and the number of RT mutations were not different between groups. Therefore, in resource-limited settings, the recommendation to perform plasma HIV-1 RNA measurement once yearly in patients on a stable antiretroviral regimen is justified.

HIV-specific and non-specific immune responses are crucial in the immunopathogenesis of HIV infection. Therefore, the objective of our study was to analyze the frequency and functional status of HIV-specific CD8+ T cells and the expression of non-specific activation markers on CD8+ T cells in HIV+ patients, and to assess the effects of combined antiretroviral treatment (cART). We examined 28 HIV+ patients, including 13 patients not receiving therapy and 15 patients on cART therapy using ELISpot assay and flow cytometry with intracellular and MHC tetramer staining. MHC tetramers detected HIV-specific CD8+ T cells in 6 HIV+ patients on cART and in 7 untreated individuals; the ELISpot method detected these cells in 5 untreated HIV+ individuals only. Reduced intracellular IFN-and#947; and IL-2 production by HIV-specific CD8+ T cells was detected in both treated and untreated HIV+ patients, and multifunctional CD8+ T cells simultaneously producing these cytokines were not found in any patient. In contrary to these findings, the percentage of CD8+ T cells expressing CD38 and HLA-DR was significantly higher in untreated patients as compared to HIV+ patients on cART. Together, these results suggest that the alterations of HIV-specific immunity are not influenced by the therapy of HIV infection; whereas, the non-specific chronic immune activation is down-regulated by cART.

In Vitro Anti-HIV-1 Activity of the Aqueous Extract of Asterina Pectinifera by Fatih Karadeniz, Mustafa Zafer Karagozlu, Chang-Suk Kong, Se-Kwon Kim (95-102).
An aqueous extract of starfish, Asterina pectinifera, was investigated for its anti-HIV-1 efficiency in vitro on human T-cell lines. A. pectinifera significantly maintained the viability of HIV-infected cells as much as 86and#x25; of the untreated infected control cells at the non-toxic concentrations (0.054 mg/mL) in CEM-SS cells. Anti-HIV-1 activity of A. pectinifera extract was further supported by quantification of syncytia formation, reverse transcriptase activity and Western blot analysis in C8166, CEM-SS and H9 cells, respectively. Current results demonstrated a notable inhibition of HIV-1 induced syncytia formation and HIV-1 reverse transcriptase activity assay with EC50 of 0.71 mg/mL and 0.65 mg/mL, respectively. Moreover, A. pectinifera extract treatment decreased the production of p24 protein and gene expression of HIV-1 viral infection factor in a dose-dependent manner according to immunoblot and reverse transcription polymerase chain reaction analysis. In the light of current study, it can be concluded that A. pectinifera contains highly potential anti-HIV-1 components and a further investigation for active compound isolation is urged.

Factors Associated with HIV Virologic Failure Among Patients on HAART for One Year at Three Sentinel Surveillance Sites in China by Xia Wang, Liting Yang, Huiqin Li, La Zuo, Shujia Liang, Wei Liu, Yonghui Dong, Shaomin Yang, Hong Shang, Jingyun Li, Laiyi Kang, Ping Zhong, Wei Zheng, Lingjie Liao, Hui Xing, Ray Y. Chen, Yuhua Ruan, Yiming Shao (103-111).
Background: Emerging HIV drug resistance (HIVDR) poses a growing threat to the long-term success and durability of highly active antiretroviral therapy (HAART). Objective: To understand the development of HIVDR and estimate the proportion of potential HIVDR and its associated risk factors among the patients on HAART for one year. Methods: Antiretroviral-naive patients and#x2265;18 years old were invited to participate in this one-year prospective study from seven clinics in Yunnan, Guangxi, and Xinjiang provinces. A questionnaire and blood draw were collected at baseline and 12 month follow-up. The protocol used was modified slightly from the WHO Protocol for Surveys of HIV Drug Resistance Emerging During Treatment and Related Program Factors in Sentinel ART Sites in Resource-limited Settings. Results: 435 patients were included in the study, of whom 351 (80.7and#x25;) were retained at 12 months. The median baseline CD4 cell count of 351 patients retained at 12 months was 132 cells/mm3, which increased to 305 cells/mm3 at 12 months (P andlt; 0.0001), with those from Yunnan and Guangxi receiving d4T/3TC/NVP and Xinjiang receiving AZT/3TC/NVP. Of the total 435 subjects, 417 met the WHO guideline for classification of outcomes based on endpoints, of whom 310 (75.3and#x25;) had a viral load andlt; 1000 copies/ml at 12 months (HIVDR prevention), 17 (4.1and#x25;) had a viral load and#x2265; 1000 copies/ml at 12 months and at least one resistance mutation identified, and 90 (21.6and#x25;) were classified as potential HIVDR, including 24 with viral loadsand#x2265;1000 copies/ml at 12 months but no drug resistance mutations, 42 who were lost to followup, and 24 who had discontinued ART by 12 months. In a logistic regression analysis, patients who self-reported missing doses in the previous month were 8.0 fold (95and#x25; CI 3.1-20.9) more likely to develop virologic failure than those who did not. and those from Xinjiang were 12.6 fold (95and#x25; CI 5.3-29.8) more likely to fail compared to those from Yunnan and Guangxi. Patients with baseline viral load > 100000 were 3.2 fold (95and#x25; CI 1.4-6.9) more likely to fail than those whose baseline viral loadand#x2264;100000. Why Xinjiang was associated with virologic failure was not clear but may be related to the demographics of the participants from Xinjiang, being significantly more IDUs, poorer, and less adherent than those from Yunnan and Guangxi. Conclusions: Although successful virologic outcomes were seen in the vast majority (75.3and#x25;) of those treated at one year, virologic failure continues to be a problem particularly among those less adherent and from Xinjiang. Additional data are needed to understand the generalizability of these results, particularly those related to Xinjiang. For IDUs, enhancing adherence to HAART and considering the treatment of drug addiction as an integral part of the treatment for HIV infection should be considered. As China's National Free Antiretroviral Treatment Program continues to mature and improve, ramping up treatment in these settings may be important considerations to the long-term success of the program.

Studies on the association between SDF1 genotype and HIV-1 susceptibility have generated inconclusive results. Therefore, we conducted a meta-analysis to summarize the findings of different studies. Articles reporting SDF1 gene polymorphisms among HIV-1 infected patients and controls were searched from PubMed up to June 2010. Odds ratios (ORs) with 95and#x25; confidence intervals (CIs) were applied to assess the association of SDF1 genotype with HIV-1 susceptibility. As a result, 13 studies with 2421 cases and 3283 controls were included in the meta-analysis. Compared with the wild-type SDF1 homozygotes, the pooled OR for SDF1 heterozygotes and SDF1-3'A homozygotes were 1.07 (95and#x25; CI, 0.79-1.45), 1.38 (95and#x25; CI, 0.71-2.69) among exposed uninfected controls and 0.89 (95and#x25; CI, 0.75-1.07), 1.15 (95and#x25; CI, 0.80-1.63) among healthy controls. In conclusion, no statistically significant association between SDF1 genotype and HIV-1 susceptibility was detected in any models. Our data suggested that SDF1 genotype might have limited effect on HIV-1 susceptibility.

HIV-Infected Patients and Liver Transplantation: Who, When and Why by Marcello Tavio, Paolo Grossi, Umberto Baccarani, Luigia Scudeller, Federico Pea, Massimiliano Berretta, Gianluigi Adani, Marco Vivarelli, Alessandra Riva, Umberto Tirelli, Vittorio Bresadola, Pierluigi Viale, Andrea Risaliti (120-127).
Well into the 25th year of the HIV pandemics, and into the 15th year of the highly active antiretroviral therapy (HAART) era, liver transplantation (LT) in the HIV population might be viewed as both a problem and an opportunity. It is still a problem when we consider that only a small proportion of all HIV-infected patients with end stage liver disease (ESLD) will have access to this precious and limited resource. But, in the face of the continuous HAART refinements, that will probably expand in the future the pool of potential HIV- organ recipients, LT is also an opportunity. Considering the poor results observed in a subset of HIV/HCV coinfected patients with an ESLD in comparison to HCV monoinfected ones, LT is still a problem. But it is an opportunity if large and well designed clinical trials will reveal favorable prognostic factors associated to the subset of HIV/HCV coinfected patients that may undergo LT with satisfactory results. Available data with good evidence presently support the practice of LT in HIV population. Thus, the issue is no longer and#x201C;whether it is correct to transplant HIV-infected patientsand#x201D;, but and#x201C;who are the patients that can be safely transplantedand#x201D; and and#x201C;when is the most correct timing to perform the surgical procedureand#x201D;. Indeed, the benefits of LT in HIV-infected patients, especially in terms of mid- and long-term patient and graft survival, are strictly related to patient selection and correct timing for transplantation. Aim of this article is to review some of the issues concerning HIV infection and LT, particularly with regard the opportunity of LT option in HIV setting and the most appropriate evaluation of an HIV-infected candidate for LT.

Non-Alcoholic Fatty Liver Disease in HIV Infection Associated with Altered Hepatic Fatty Acid Composition by Bianca M. Arendt, Saira S. Mohammed, David W.L. Ma, Elaheh Aghdassi, Irving E. Salit, David K.H. Wong, Maha Guindi, Morris Sherman, Elizabeth J. Heathcote, Johane P. Allard (128-135).
Hepatic fatty acid (FA) composition, especially a reduction in n-3 polyunsaturated FA (PUFA) may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is common in HIV-infection. In a cross-sectional study we compared hepatic FA composition between 20 HIV-infected men with NAFLD (HIV/NAFLD), 21 HIVnegative men with NAFLD (NAFLD), and 7 healthy controls. Within HIV/NAFLD we compared simple steatosis (HIV/SS) to steatohepatitis (HIV/NASH). FA composition in liver and erythrocytes, oxidative stress, diet, and exercise were assessed. Major findings (P andlt; 0.05) were: 1) higher hepatic n-6/n-3 ratio in HIV/NAFLD [median (range)] [8.08 (1.08-21.52)] compared to controls [5.83 (3.58-6.93)] and NAFLD [5.97 (1.46-10.40)], with higher n-6 PUFA in HIV/NAFLD compared to NAFLD; 2) lower n-3 PUFA in erythrocytes (moland#x25;), a marker for dietary intake, in HIV/NAFLD [5.26 (1.04-11.75)] compared to controls [8.92 (4.79-12.67)]; 3) the ratios of long-chain PUFA products to essential FA precursors of the n-6 and n-3 series were lower in HIV/NAFLD and NAFLD compared to controls. In contrast, the ratio of oleic/stearic acid was higher in HIV/NAFLD compared to the other groups. These ratios are indirect markers of enzymatic FA desaturation and elongation. Hepatic PUFA, especially biologically active long-chain PUFA, were also lower in HIV/NASH compared to HIV/SS. Oxidative stress was not different among the groups. We conclude that HIV/NAFLD is associated with altered hepatic FA composition. Changes may be due to impaired FA metabolism or suboptimal n-3 PUFA intake. The potential role of n-3 PUFA (e.g. fish oil) to treat or prevent HIV/NAFLD warrants further investigation.

The Dynamic Face of HIV-1 Subtypes Among Men who have Sex with Men in Beijing, China by Wanhai Wang, Jianqing Xu, Shulin Jiang, Kai Yang, Zhefeng Meng, Yan Ma, Mingkui Li, Xiaoxi Zhang, Yiming Shao, Fengmin Zhang, Xiaoyan Zhang (136-139).
The rapid increase of HIV-1 prevalence among Chinese men who have sex with men (MSM) provides an impetus for the acquisition of molecular epidemiologic information from this population. We conducted four serial crosssectional surveys during the years 2005-2009 and observed that the composition of HIV-1 subtypes was dynamically changing from clade B to CRF01_AE from years 2005-2009. HIV-1 infection in this population includes the persistent circulation of multiple HIV-1 subtypes and complex new recombinants.