Current HIV Research - Volume 7, Issue 4, 2009

Drug use and HIV/AIDS are global public health issues. The World Health Organization (WHO) estimates that up to 30% of HIV infections are related to drug use and associated behaviors. The intersection, of the twin epidemics of HIV and drug/alcohol use, results in difficult medical management issues for the health care providers and researchers who work in the expanding global HIV prevention and treatment fields. Access to care and treatment, medication adherence to multiple therapeutic regimens, and concomitant drug -drug interactions of prescribed treatments are difficult barriers for drug users to overcome without directed interventions. Injection drug users are frequently disenfranchised from medical care and suffer sigma and discrimination creating additional barriers to care and treatment for their drug abuse and dependence as well as HIV infection. In an increasing number of studies, medication assisted treatment of drug abuse and dependence has been shown to be an important HIV prevention intervention. Controlling the global transmission of HIV will require further investment in evidence-based interventions and programs to enhance access to care and treatment of individuals who abuse illicit drugs and alcohol. In this review, we present the cumulative evidence of the importance of medication assisted treatment in the prevention, care, and treatment of HIV infected individuals who also abuse drugs and alcohol.

The spectrum of complications emerging in successfully treated HIV-infected patients has dramatically changed since the advent of HAART. Typical AIDS-defining illnesses have been substituted by new comorbid conditions that threaten even those patients who maintain virologic suppression. Proper management of cardiovascular risk, and early diagnosis of AIDS-related and, particularly, non-AIDS-related malignancies (including papilomavirus-related neoplasms) must be introduced into the routine of care. Hot areas of investigation include HIV-associated neurocognitive disorders, hepatitis B and C coinfection, non-alcoholic fatty liver disease, progressive multifocal leukoencephalopathy and tuberculosis. Bone and kidney long-term toxicities and lipoatrophy remain as issues of paramount importance. The identification and early treatment of immune reconstitution disease is also of major interest, specially in those patients starting their antiretroviral treatment with severe CD4 cell depletion. The present review focuses on these twelve areas of increasing interest for physicians currently facing successfully treated HIV+ patients.

Objective: To characterize the functional properties of natural autoantibodies capable of preventing in vitro infection by HIV-1, present in normal human serum (NHS), and denoted as IgG-reactive antibodies. Methods: IgG-reactive antibodies were affinity purified both from normal human serum (NHS) and from a GammaBind G Sepharose Flowthrough (GBF) fraction of NHS by affinity chromatography on IgG coupled to CNBr-activated Sepharose (IgG-Sepharose). Results: The GBF fraction was shown, by Capture ELISA relative to isotype-matched standards, to contain in addition to IgM and IgA isotypes, a low but constant level of IgG isotype. About 15% of the GBF fraction's IgG, compared to only about 0.3% of the NHS IgG, was affinity purified on IgG-Sepharose. On IgG subclass analysis, in contrast to the characteristic dominance of IgG1 in pooled NHS, the IgG-reactive antibodies obtained from NHS and from the GBF fraction each showed a dominance of IgG2. Western blot analysis confirmed the abundance of IgG2, a major IgG subclass reactive against carbohydrate antigens, and showed the presence of IgG2 dimers. The IgG-reactive antibodies separated from the GBF fraction were able to neutralize HIV-1BaL strain with approaching 100% and 80% effectiveness at 2μg/ml and 0.6μg/ml, respectively, as well as the primary isolates HIV-1NDK (X4-tropic isolate) and HIV-1JR-CSF (R5-tropic isolate) with an IC50 between 0.4 μg/ml and 1.8 μg/ml for two different preparations. Conclusion: These findings further support our previous proposal for IgG-reactive antibody preparations to be used in the treatment of HIV-1 infected individuals.

Objective: To investigate the molecular phenotype of the AIDS-onset delaying polymorphism in CXCL12β 3'UTR (rs1801157). Methods: The 3'UTRs of the CXCL12β isoform containing the A or G polymorphic variants were cloned downstream of the Luciferase gene under the control of the CXCL12 promoter. The plasmids were transfected in U373 and LC5 cells and the polymorphism phenotype was evaluated in terms of Luciferase activity and mRNA stability. Results: The 3'A genotype compared to 3'G leads to an increased luciferase activity in unstimulated and PMA+Ionomycin treated cells both in astrocytes (p= 0,0002, p = 0,02) and fibroblasts (p = 0,002, p = 0,03). The mRNA containing the 3'A variant have two-fold longer half-life compared to the 3'G variant (p = 6,99E-7). Conclusions: CXCL12β 3'A polymorphism, previously associated with resistance to AIDS progression and other diseases, leads to increased levels of CXCL12 mRNA, the results presented here demonstrate that this effect is a consequence of an enhanced mRNA stability. Our data contribute to characterize the CXCL12 as a potential pharmacological target in AIDS, autoimmune diseases and cancer.

This study describes the current situation and projects dynamic trends for HIV prevalence in a highly endemic area of China, Liangshan Prefecture, Sichuan Province. Epidemiological, behavioral, and population census data from multiple sources were analyzed to extract input for an Asian Epidemic Model (AEM). Fitting curves to historical trends in HIV prevalence were used as a baseline, and future intervention scenarios were explored using the AEM. For 2007, modeled data suggested ≈0.5% adult HIV prevalence in Liangshan, with an estimated 17,450 people living with HIV/AIDS and 3,400 new infections. With current high risk behaviors, the model predicts that adult prevalence will rise to 1.5% by 2020. Increased condom use and clean needle exchange among injection drug users (IDUs) have slowed the epidemic. The source of new HIV infections will change from a preponderance of IDU-related infections in 2007 (65.9%) to a mixed epidemic in 2020 (general population heterosexuals 45.2%, IDU 38.6%, homosexual transmission between men 12.7%, female sex workers and their clients 3.5%). We anticipate rising prevalence, stable incidence, and higher representation of sexual transmission over time. Prevention investments should target specific interventions toward subgroups at highest risk, given that both IDUs and men who have sex with men will likely represent a majority of cases and serve as a bridge population.

Antiretroviral therapy is standard treatment for HIV-infected patients. Such therapy has decreased mortality and morbidity, but treatment success is often jeopardized by the emergence of viral drug resistance. Moreover, in recent years there has been a reported rise in the incidence of transmitted drug resistance, highlighting the importance of pretreatment resistance screening. In this report, we describe the development and utility of a sensitive multiplex approach for detecting mutations conferring drug resistance to HIV-1 reverse transcriptase inhibitors. This protocol, termed HIVSNaPshot, utilizes a multiplex primer extension assay with capillary electrophoresis reporting altered nucleotides at nine important drug resistance mutation positions. Mutations were successfully detected to levels of 5% in viral quasispecies populations. Furthermore, although developed and optimised for HIV-1 subtype B, drug resistance mutations could also be detected in most non-B subtypes. Comparison of the HIV-SNaPshot with the commercial Viroseq genotyping system in 10 patients gave similar results, but importantly, additional resistance mutations were identified in several patients by the HIV-SNaPshot assay. Thus, the HIV-SNaPshot is a method capable to support standard genotyping for the determination of minority HIV-1 resistance mutations, with equivalent and perhaps greater sensitivity than Viroseq.

The prospects for expanded access to antiretroviral therapy (ART) in resource-poor settings have greatly improved as a result of global and national efforts to reduce the cost of antiretroviral drugs (ARV), growing availability of cheaper generics, and increased financing available from the Global Funds like Medicines Sans Frontieres. Indian health set-up provides drugs free-of-cost to HIV infected patients through government network and also through open-market to those who intend to have personalized care. Post-2005, implementation of WTO agreement on TRIPS is expected to have a significant impact on pricing and availability of generic ARV. The study has been planned to explore the trends and gaps in availability & accessibility of ARV in India. The trends in per-patient-per-year (PPPY) cost of individual ARV and treatment regimes were also explored. The epidemiological data demonstrated stabilization of the epidemic in India. Most ARV are available in India by the generic manufacturers with a median drug lag period of 2.05 years (Range 0.75- 6.51 years). There is a significant price difference in drugs available from generic and originator companies. Prices for patented and generic ARV in India reflect price negotiations that have taken place since the introduction of drugs in the country, still most of the ARVs are available at a much higher cost in the market [median 2.6 times (range 1-7)]. The perpatient per year (PPPY) cost of providing first-line regime in 2008 has decreased 2.75 times from that in 2003. The analysis shows the stabilization of prices of all drugs after 2006.HIV spending in India has seen a growth of 26 percent and 28 percent in 2005-06 and 2006-07 respectively. Still, the expected expenditure to cover the whole patient population needing therapy is considerably higher than the actual expenditure incurred for providing ARV. Despite the price reductions and availability of ARV at a lower cost through agencies like MSF, there is a large gap in the expenditure incurred and patient population covered. These trends may foreshadow future AIDS treatment cost trends in the country as more people start treatment, AIDS patients live longer and move from first-line to second and third-line treatment, AIDS treatment becomes more complex, generic competition emerges, and newer patented drugs become available.

Although very inefficient, sexual transmission of HIV-1 is responsible for more than 80% of infections worldwide. Yet, the presence of HIV in spermatozoa has been a matter of debate. The aim of this study was to evaluate the presence of HIV nucleic acids and the distribution of mannose receptors in sperm cells, and to determine the semen parameters and cytokine levels in ejaculates from HIV-positive patients. The presence of non-seminal cells in purified sperm was revealed by light microscopy, flow cytometry and RT-PCR. HIV nucleic acids were evaluated by nested PCR; the distributions of mannose receptors on the surface of the sperm and cytokine levels in ejaculates were determined by fluorescence microscopy and flow cytometry respectively. Sperm characteristics were determined by conventional methods. HIV DNA was detected in 69.2% of purified sperm from HIV-positive men; in contrast all purified sperm were negative for HIV RNA. The distribution of mannose receptors and cytokine levels in HIV-1-positive men were similar to uninfected individuals. Using the Principal Component Analysis (PCA) method, it was possible to determine that semen parameters of HIV-positive men exhibit different distributions compared to HIV-negative individuals. Finally, these results indicate that viral DNA is present in purified sperm from HIV-positive men and that HIV infection of spermatozoa could be associated with lower seminal parameters as demonstrated by the PCA method. The similar distribution of mannose receptors between infected and uninfected individuals suggests that sperm cells from infected individuals interact normally with oocytes.

Tipranavir, a non-peptidic protease inhibitor which shows in vitro efficacy against some HIV-1-resistant strains, can be used in salvage therapies for multi-experienced HIV patients due to its peculiar resistance profile including 21 mutations at 16 protease positions according to International AIDS Society (IAS). Other genotypic scores, however, which attribute a different weight to single amino-acid substitutions, have been recently proposed. To validate the clinical utility of four different genotypic scores for selecting tipranavir responders, the baseline resistance pattern of 176 HIV heavily experienced patients was correlated with virological success (HIV-RNA<50 copies/ml) after 24 weeks of a new treatment based on tipranavir/ritonavir. Virological suppression after 24 weeks was reached by 42.5% of patients. With univariate analysis, genotypic scores were all associated with outcome but showed a low accuracy with ROC analysis, with the weighted score (WS) by Scherer et al. demonstrating the best performance with an AUC of 68%. Only 52% of patients classified as susceptible (WS®3) responded to the new therapy. The following variables were significantly associated (p<0.05) to failure with multivariate analysis: WS, log peak of HIV-RNA, IAS mutations: L33F, I54AMV, Q58E, and non-IAS mutation: N37DES. On the contrary, the use of T20 in T20-naïve patients and the V82AFSI and F53LY non-IAS mutations were associated with virological success. The study suggests that even if the “weighted” scores are able to interpret correctly the antiretroviral resistance profile of multi-experienced patients, it is difficult to individuate a cut-off which can be easily applied to this population for discriminating responders.

Successfully treated sudden cardiac death due to malignant arrhythmia related to HIV myocarditis in a young male with favorable clinical and virological profile is not described in current literature. HIV myocarditis as a possible cause of malignant ventricular arrhythmia and sudden cardiac death is discussed.

Most of the HIV-infected long term survivors show strong CD8+ cell noncytotoxic antiviral response (CNAR) that plays as an important factor for maintaining the relative healthy state of infected individuals. HIV infected former blood donors (FBDs) in Anhui, China are the unique population that considered infected by the same or a related HIV strain by the same exposure route, and is better to be studied for viral and host immunological factors associated with disease progression, such as CNAR. We examined CNAR in 63 asymptomatic untreated HIV infected FBDs with different CD4+ cell counts and plasma viral loads. The average CD8+ : CD4+ cell ratio to reach 90% suppression of HIV replication in the groups with CD4+ cell counts of >500, 300-500 and <300 cells/μl were 0.85 : 1, 1.47 : 1 and 1.88 : 1 respectively (P<0.0001). The average CD8+ : CD4+ cell ratio to reach 90% suppression of HIV replication was 1.07 : 1 and 1.66 : 1 in the group with plasma viral load of <30,000 and >30,000 RNA copy/ml respectively (P=0.0002). The results indicated that CNAR activity in long-term HIV-1 infected FBDs correlates directly with CD4+ cell counts, and correlates reversely with plasma viral loads. Our findings in long term infected FBDs confirm the clinical relevancy of CNAR and suggest that CNAR could be an additional marker to help determine the optimal time for starting therapy in HIV infected person.

Background: HIV treatment programs in Africa typically approach all enrolling patients uniformly. Growing numbers of patients are antiretroviral experienced. Defining patients on the basis of antiretroviral experience may inform enrollment practices, particularly if medical outcomes differ. Methods: Baseline and follow-up measures (CD4, weight change, and survival) were compared in a retrospective analysis between antiretroviral-naive (ARV-N) and antiretroviral experience (ARV-E) patients enrolled at the Coptic Hope Center for Infectious Diseases in Nairobi, Kenya and followed between January 2004 and August 2006. Results: 1,307 ARV-N and 962 ARV-E patients receiving highly active antiretroviral therapy (HAART) were followed for median of 9 months (interquartile range: 4-16 months). Compared to ARV-N, ARV-E had substantially higher CD4 count (median cells/mm3, 193 versus 95, P < 0.001) and weight (median kg, 62 versus 57, P < 0.001) at baseline, and lower rates of change in CD4 (-9.2 cells/mm3/month; 95% CI, -11.4 - -7.0) and weight (-0.24 kg/month; 95% CI, -0.35 - - 0.14) over 12 months. Mortality was significantly higher in ARV-N than ARV-E (P = 0.001). Conclusions: ARV-E patients form a growing group that differs significantly from ARV-N patients and requires a distinct approach from ARV-N clients. Systematic approaches to streamline care of ARV-E patients may allow focused attention on early ARV-N clients whose mortality risks are substantially higher.

Chronic hepatitis C is frequent and aggressive in HIV-positive patients. Identification of early predictors of response to anti-HCV therapy is needed for a lower rate of response and higher discontinuations, compared to HCV mono-infected subjects. The aim of our study was to evaluate the predictive value of virological response (VR) at week 4-8-12 of Pegylated interferon alpha-2b (PEG-IFN) plus ribavirin (RBV) on sustained virological response (SVR) in HIV-HCV co-infected patients. 100 patients were treated with PEG-IFN (1.5 mcg/Kg/w) plus RBV (>/=10.6 mg/kg/d) and randomized for 24-48 or 48-72 weeks, respectively for genotype 2-3 and 1-4, in case of response (HCV-RNA PCR negativity) at the end of standard therapy (24 weeks for genotype 2-3, 48 weeks for genotype 1-4). Transcription-Mediated Amplification (TMA) assay for HCV-RNA was also applied. 27 patients reached end-of-treatment response (9 genotype 1-4, 18 genotype 2-3), 21 achieved SVR (8 genotype 1-4, 13 genotype 2-3). 35 patients dropped, 15 due to side-effects. SVR was statistically related to lower baseline HCV-RNA and to VR at week 4-8-12, with PPV 64%, 53% and 58%, and NPV 81%, 96% and 88%, respectively. In 27 patients, TMA was performed and confirmed standard PCR, except in two cases of relapse, who were PCR negative but TMA positive at week-12. In conclusion, VR at week 8 showed the highest NPV on SVR (96%). The study of viral kinetics requires further investigations in HIV-positive patients to guarantee a cost-effective therapy and to guide individually the duration of treatment. In this setting, TMA might be useful.

Highly active antiretroviral therapy (HAART) for HIV-infection is associated with lipodystrophy, insulin resistance, increased prevalence of disturbances in glucose tolerance and diabetes, hyperlipidemia and increased cardiovascular risk. Whether dietary intake influences total body fat, visceral fat, insulin resistance, glucose metabolism, lipid metabolism and circulating inflammatory markers in HIV-infected subjects with lipodystrophy is unclear and the focus of this report. We examined the dietary intake of 106 male HIV-infected HAART-recipients with lipodystrophy, enrolled in a study of the effects of rosiglitazone. All subjects had normal glucose tolerance. Dietary intakes were determined at study entry using Food Frequency Questionnaires and examined cross-sectionally against body composition by dual-energy Xray absorptiometry, visceral obesity by computed tomography, fasting glucose, insulin, lipids, adiponectin, leptin, insulin resistance (by HOMA). Energy underreporters were identified and excluded. After exclusion of underreporters (n = 22) we found no relationships between diet composition (% dietary fat, %carbohydrate) and BMI, %body fat and visceral adiposity (p>0.3). Only modest relationships were found between BMI and fat subtypes: polyunsaturated fats (g/day) (r = 0.14, p = 0.007), monounsaturated fat (g/d) (r = 0.06, p = 0.001), saturated fat (g/d) (r = 0.02, p>0.0001). Only saturated fat related to % total body fat (g/d: r = 0.08, p<0.0001, %energy intake: r = 0.16, p<0.0001). No nutrient related to visceral adiposity by CT. Dietary fat intake (expressed as a % of energy intake) was not related to total cholesterol, HDL cholesterol, triglycerides, fasting insulin, glucose, leptin, adiponectin or HOMA-IR (p>0.4). Fat subtype did not relate to fasting insulin, insulin resistance, total cholesterol, HDL, triglycerides, glucose, adiponectin. In conclusion, there are weak relationships between saturated fat intake and adiposity in HIV-infected subjects with lipodystrophy, using gold standard measures of body fat. There were no relationships between nutrient intake and visceral adiposity, any measure of glucose metabolism, insulin resistance or adipokines. Only interventional, prospective studies will determine whether any nutritional strategy can assist in ameliorating the metabolic complications associated with HIV lipodystrophy.

Background: Smoking prevalence is very high among people living with HIV/AIDS, and smoking is riskier for them than for HIV-seronegative people. Promoting smoking cessation among HIV-infected people is therefore an emerging public health priority. Raising cigarette prices is usually considered as one of the most effective ways to reduce smoking, but its effectiveness has never been studied among HIV-infected smokers. Methods: We studied the impact of cigarette price increases among HIV-infected smokers, with data extracted from the French cohort study APROCO-COPILOTE conducted between 1997 and 2007 among 1,146 patients. Data regarding respondents' smoking status was collected every 8 months over the first 5 years, and every 12 months thereafter. Results: We found striking differences across transmission groups regarding socio-demographic background and smoking prevalence. The Intravenous Drug Use (IDU) group was characterised by a lower socioeconomic status, a higher smoking prevalence and a smaller decrease in this prevalence over the period 1997-2007. The homosexual group had a higher socioeconomic status, an intermediate smoking prevalence in 1997, and the highest rate of smoking decrease. In the dynamic multivariate analysis, smoking remained correlated with indicators of socioeconomic disadvantage and with infection through IDU. Aging and cigarette price increase had a negative impact on smoking among the homosexual group, but not for the IDU group. Conclusion: Among seropositive people, just as for the general population, poor smokers are poor quitters. Public health authorities should consider interventions which are not smoking-specific, but which contribute to improve the living conditions of the most deprived HIV-infected smokers.