Current HIV Research - Volume 9, Issue 4, 2011

The existence of stable, transcriptionally silent human immunodeficiency virus (HIV) in latently infected cells represents a major obstacle to acquired immune deficiency syndrome (AIDS) therapy. Histone deacetylase (HDAC) can inhibit histone acetylation, resulting in HIV-1 provirus transcription silence. Apicidin, a widely used antiparasitic drug, exhibits antiparasitic activity by inhibiting HDAC. Using the latently infected A10.6 cell line, we describe the dose- and time-dependent manner in which Apicidin reverses HIV-1 latency. We found that Apicidin can synergize with trichostatin A (TSA) to activate HIV-1 gene expression. Chromatin immunoprecipitation (ChIP) assay further indicates that Apicidin induces HIV-1 reactivation by increasing the acetylation levels of H3 and H4 at nucleosome 1 in HIV-1 long terminal repeats (LTR). Our research reveals a potent activator for reactivating latent HIV-1 and shows promise for HIV-1 therapy.

Extracellular adenosine triphosphate (eATP) is a potent molecule that has the capacity to modulate various aspects of cell functions including gene expression. This element of modulation is essential to the role of ATP as a therapeutic agent. The hypothesis presented is that ATP can have an important impact on the treatment of HIV infection. This is supported in part by published research, although a much greater role for ATP is suggested than prior authors ever thought possible. ATP has the ability to enhance the immune system and could thus improve the host's own defense mechanisms to eradicate the virus-infected cells and restore normal immune function. This could provide effective therapy when used in conjunction with highly active antiretroviral therapies (HAART) to eliminate the latently infected cells. The key lies in applying ATP through the methodology described. This article presents a strategy for using ATP therapeutically along with background evidence to substantiate the importance of using ATP in the treatment of HIV infection.

Saliva may provide interesting advantages as matrix for compliance measurements, pharmacokinetic studies and therapeutic drug monitoring in resource limited countries. We investigated the feasibility of using saliva for compliance monitoring of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) in 29 HIV-1 infected patients from Rwanda. ZDV, 3TC and NVP drug levels were quantified by an LC/MS-MS method in plasma and stimulated saliva samples and compared using Bland-Altman analysis. Seven patients demonstrated undetectable saliva ZDV levels while five out of these seven also showed no 3TC salivary concentrations. For the other samples, we observed a good agreement between salivary and plasma concentrations of each antiretroviral drug. A significant relation between the difference in saliva and plasma ZDV concentrations and the average ZDV concentration in the two matrices was deduced as follows: y = -380.15 + 1.79 x. The log saliva and plasma concentration difference of both 3TC and NVP was consistent across the range of average log concentration. Overall, we showed large agreement limits suggesting a wide inter patient variability that may result in non-reliable plasma level predictions from saliva drug measurements. Therefore, our results indicate that saliva may serve as a valuable tool only for NVP compliance testing because of its high salivary concentration.

We aimed to evaluate immunological, virological and clinical response to HAART, as well as all-cause mortality, in treatment-naive patients with a diagnosis of tuberculosis (TB) in the prior 6 months, compared to subjects with another AIDS-defining illness (ADI) or event-free individuals in an open, prospective and multicenter hospital-based cohort of HIV-infected naive adults (2004-2008). All cause mortality rates were calculated by Cox regression models. Among 4407 patients, 2400 (54.5%) started HAART: 110 (4.6%) had had previous TB and 414 (17.3%) another ADI. Median time from TB diagnosis to inititation of HAART was 53 days (IQR: 25.75-83.25), and for other ADI was 22 days (IQR: 8-42). Overall, 151 (6.3%) patients developed a new ADI during follow-up; 63% reached virological suppression and 69.4% had increases of ≥50 CD4+/μl, at 6 months. No statistically significant differences were found according to a previous history of TB or another ADI. Overall, 85 subjects died in 4031 person-years of follow-up with a mortality rate of 2.1 (95%CI: 1.7-2.6). When compared to subjects who started HAART in the absence of a previous ADI (HR 1), a prior diagnosis of an ADI other than TB was significantly associated with an increased risk of death. (HR 1.6; 95%CI: 1.1-2.3), but not a diagnosis of TB (HR 1.15; 95%CI: 0.5-2.5). In conclusion, a previous diagnosis of TB or another ADI before HAART did not compromise short-term virological and immunological response to treatment. A prior diagnosis of an ADI different to TB significantly increased all cause mortality.

The use of HIV protease inhibitors (PIs) as part of antiretroviral therapy in the treatment of HIV-1 infection may be associated with an increased risk of bleeding. This prospective, randomized, open-label trial in healthy volunteers compared the effects of tipranavir/ritonavir (TPV/r), darunavir/ritonavir (DRV/r), and ritonavir (RTV) alone on platelet aggregation after a single dose and at steady-state concentrations. Subjects were selected on the basis of normal platelet aggregation and arachidonic acid (AA)-induced platelet aggregation inhibition after administration of a single 325-mg dose of aspirin. All 3 PI therapies were administered twice daily for 10 days. In some but not all subjects, TPV/r inhibited AA-induced platelet aggregation and prolonged PFA-100® closure time with collagen-epinephrine cartridge, which was of lesser magnitude and consistency compared with aspirin, but greater when compared to DRV/r and RTV. At least 2 subjects in each treatment arm showed complete inhibition of AA-induced platelet aggregation on treatment, and the magnitude of change in all platelet-function tests did not correlate with PI plasma concentrations. Effects of TPV/r on platelet aggregation were reversed 24 hours after the last TPV/r dose. None of the PI treatments tested were associated with increases in bleeding time, decreases in plasma coagulation factors, or increase in fibrinolysis. There was large inter-patient variability in antiplatelet effect for all PI treatments, ranging from no effect to complete inhibition of AA-induced platelet aggregation.

South Africa has the highest prevalence of human immunodeficiency virus (HIV) infection in the world. The improved life expectancy, due to the recent introduction of highly active antiretroviral therapy (HAART), may lead to an increased health burden related to metabolic disorders, resulting in an increased pressure on health-care services. The main objective of this study was to determine the prevalence of hypertension, diabetes, obesity and dyslipidemia in a sample of HAART-treated HIV infected patients, attending an HIV clinic in the Gauteng province. This was a cross-sectional study of 304 HIV positive patients enrolled between January 2009 and March 2009, including patients aged 18 to 45 years, on HAART for more than one year. Hypertension prevalence was 19.1% (95% confidence interval (CI) 14.7-23.5): 23.9% in men and 17.7% in women (P=0.10). Diabetes was diagnosed in 4 women. Hypercholesterolemia (total cholesterol >5.00 mmol/mL) was found in 32.2% (95% CI 27.0-37.5), low HDL cholesterol (<1.20 mmol/mL) in 45.7% (95% CI 40.1-51.3) and elevated LDL cholesterol (>4.10 mmol/mL) in 9.5% (95% CI 6.2-12.8); these prevalences were not different between sexes, whereas hypertriglyceridemia (>2.25 mmol(mL) (15.8%, 95% CI 11.7-19.9) was significantly more frequent in men (28.4% versus 12.2%, P=0.002). TC and LDL-C were positively correlated with CD4+ cell count (r=0.13, P=0.03 and r=0.12, P=0.03). In this sample, the traditional risk factors for cardiovascular disease had a high prevalence, despite the young age of our patients. Women seemed to be at higher risk than man, unlike other HIV populations where these comparisons were made (Uganda, Italy and Norway). Obesity and lipid abnormalities, highly prevalent in the general population, also appeared related to HIV-infection and CD4+ cell count, presumably as a consequence of ART exposure. Further studies are needed in order to survey a population where HIV infection is turning into a chronic disease, with its complications.

Objective: A long-term medication adherence project was designed and implemented in an urban HIV clinic to address antiretroviral medication adherence. Design and Methods: We conducted a prospective study of patients on long-term antiretroviral therapy. Referred patients were on antiretroviral agents at least six months and had two consecutive detectable viral loads. A standarized form was utilized to assess medication adherence, including patient report, practitioner assessed barriers, and pharmacy refill history. Individualized interventions were developed to accommodate patient needs. Results: Seventy-eight patients met inclusion criteria for a total of 81 cases per study protocol. The majority of cases had an identifiable cause related to missed and/or mistimed doses. Following adherence interventions, 51 of the 81 cases (63%) experienced a successful outcome. In addition, 16 of the 27 cases (59%) without an identifiable cause became undetectable following intervention. Conclusions: This novel approach demonstrates that a proactive method for addressing barriers to long-term medication adherence yields improved patient understanding and preservation of treatment regimens.

Progression of liver fibrosis is associated with the risk of cirrhosis and end-stage liver disease. We aimed to evaluate fibrosis of the liver using three non-invasive indexes (FIB-4, Forns, and Pohl score) and its association with mortality of HCV-monoinfected and HCV/HIV-coinfected drug users. Patients and Methods: longitudinal study in patients admitted to substance abuse treatment between 1994 and 2006. Socio-demographic data, drug use characteristics, blood samples for laboratory tests, and serology for HIV and hepatitis C virus infections were collected at admission. Patients were followed-up until December 2006 and mortality was ascertained through hospital charts and death certificates. Results: Four hundred and ninety-seven patients were included (83.1% men); median age at admission was 31 years (IQR: 27-35 years). The main drugs of abuse were opiates (89.5%) and cocaine (8.3%). Thirty-two percent of patients reported daily alcohol consumption. The estimated prevalence of advanced liver fibrosis (ALF) was higher among HCV/HIVcoinfected patients (9.2% to 17.3% depending on the index analyzed) than among the HCV-monoinfected patients (3% to 3.5%). Odds ratio (OR) for ALF were 3.3 to 6.0 times higher in coinfected patients as compared to the HCVmonoinfected. After a median follow-up time of 7.7 years (IQR: 4.1-9.9 years), almost 20% of patients had died. The estimated ALF at admission was associated with an increased risk of death (RR 1.85 to 3.89 depending on the index). Among those with ALF, mortality rates were similar in HCV-monoinfected and HCV/HIV-coinfected patients, as determined by the FIB-4 and Forns indexes. Conclusions: Estimation of liver fibrosis using serum markers may help with clinical decisions to facilitate access to treatment of chronic hepatitis C in this population.

Chronic hepatitis B affects nearly 10% of HIV-infected patients. Hepatitis B virus (HBV) infection is a dynamic disease and coinfection with HIV impacts directly on the outcome of HBV infection, considerably complicating its natural history, diagnosis, and management. The aim of this study was to compare two cohorts of HBV monoinfected and HBV/HIV coinfected Iranian patients undergoing long-term lamivudine therapy from the clinical and virological aspects, as well as the frequency of detected mutations in HBV genome. To this end, HBV Pol/S regions from 72 patients were PCR-amplified and directly sequenced. Phylogenetic analysis indicated a 40-times higher risk of coinfection with ayw3 subtype of HBV genotype D rather than ayw2 subtype [P<0.001, odd: 40.66, CI: 95% (4.69-352.23)]. While no resistance mutation was detected in HBV/HIV coinfected cohort, LAM-resistance mutations (rtM204I/V in YMDD and rtL180M in FLLA polymerase motifs) were identified in 30% (9 out of 30) and 16.66% (5 out of 30) of HBV monoinfected patients (P<0.05). Moreover, several mutations (sP105A, sI110S/L, sS136Y and sP127T/L) with significant differences in the frequency were identified in the S region of both cohorts. Finally, this study found strong correlation between the type of infection (mono or coinfection) and characteristics like patient gender, ALT levels, HBV-DNA levels and HBV subtypes. These results pointed to the importance of determination of HBV variants in the management of patients and suggested that in contrary to HBV monoinfections, LAM may be still an appropriate drug for the treatment of HBV in HBV/HIV coinfected patients; however, further studies to clarify the role of HIV in HBV LAM-resistance mutations are required..

Background: Kaposi's sarcoma is commonly described in HIV/AIDS patients but usually manifests as overt skin lesions or visceral involvement. Bone involvement, particularly vertebral, is uncommon, especially when there is no adjacent cutaneous lesion but a small number of cases have been reported. Unlike many other diseases associated with HIV, Kaposi's sarcoma can occur despite a normal CD4 count. Case Presentation: A 44 year-old HIV positive Nigerian man presented with a 20 day history of severe, worsening lumbar back pain, nearly three years after an earlier diagnosis of a single cutaneous lesion consistent with Kaposi's sarcoma, for which he received chemo-radiotherapy. Despite varying previous compliance with his anti-retroviral therapy, he was thought to be taking his medications at time of presentation and his CD4 count was 408 cells/mm3. No other organ involvement was found but a pathological fracture was seen on magnetic resonance imaging affecting L1 vertebra. A CTguided needle aspiration biopsy was performed and a histological diagnosis subsequently confirmed Kaposi's sarcoma. The patient was treated with further courses of radiotherapy but had little clinical improvement. Indeed, a follow-up MRI four months later showed new involvement of a further four vertebrae, fortunately in the absence of progressive focal neurology. Conclusion: Vertebral Kaposi's sarcoma is a rare diagnosis but can be accurately diagnosed with CT or MRI imaging in conjunction with a histological diagnosis. An immunosuppressed patient presenting with bone pain should be thoroughly investigated for Kaposi's sarcoma as modern chemotherapeutic agents alongside anti-retroviral therapy may delay or prevent further devastating complications such as spinal cord compression.