Prolonged use of tenofovir in HIV/hepatitis B virus (HBV)-coinfected individuals does not lead to HBV polymerase mutations and is associated with persistence of lamivudine HBV polymerase mutations.

OBJECTIVES: The aim of the study was to identify and characterize hepatitis B virus (HBV) polymerase gene mutations associated with ongoing HBV replication in HIV/HBV-coinfected individuals receiving tenofovir (TDF). METHODS: This retrospective cross-sectional study identified 28 HIV/HBV-coinfected individuals who had received TDF for at least 3 months. All patients had samples available while receiving TDF (on-TDF), and 24 also had samples available prior to treatment (pre-TDF). Case records were reviewed to obtain clinical and virological data at the times of sampling (+/-3 months). The HBV DNA of all samples was amplified using polymerase chain reaction (PCR), and the polymerase region of PCR-positive samples was sequenced and compared with reference HBV data. RESULTS: Of the pre-TDF samples, 15 of 24 (63%) were HBV PCR positive. Of the on-TDF samples, four of 28 (14%) were HBV PCR positive (mean time on TDF 13.5 months; range 3-23 months). Lamivudine (3TC)-resistance mutations were detected in three of four (75%) of these viraemic samples. The previously identified putative TDF-resistance mutations, rtA194T+rtL180M+rtM204V, were not detected in any individual. CONCLUSIONS: Unique mutations in the HBV polymerase gene associated with TDF resistance are rare in HIV/HBV coinfection. 3TC-resistance mutations persist and a significant proportion of patients are HBV PCR positive despite the addition of TDF.

Complementary medicine use among people living with HIV/AIDS in Victoria, Australia: practices, attitudes and perceptions.

There is limited evidence suggesting the underlying reasons for the use of complementary and alternative medicines (CAMs) by people with HIV/AIDS, or individual attitudes and beliefs about the use of CAMs. Using focus groups and a survey with 151 individuals attending the HIV Clinics at The Alfred Hospital, Melbourne, we aimed to provide insights into factors that influence the use of CAMs among people living with HIV/AIDS. Roughly half (49%) of the participants had used CAMs to manage their HIV/AIDs. Users of CAMs utilized a wide range of treatments in managing their condition, but costs of the CAMs meant that users were not necessarily able to use them as much as they might have liked. Use of CAMs was based on a desire to find something beneficial rather than on being dissatisfied with conventional medicine. Further research is needed into (a) the effects of CAMs and (b) the enhancement of communication and collaboration between patients, doctors and complementary medicine practitioners.

Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993-2006.

OBJECTIVES: The aim of the study was to describe the prevalence of and risk factors for HIV-associated sensory neuropathy (HIV-SN) in 2006 [the era of stavudine, didanosine and zalcitabine (dNRTI)-sparing highly active antiretroviral therapy (HAART)] and to compare our findings with data obtained in the same clinic in 1993 (pre-HAART) and 2001 (frequent use of dNRTI-containing HAART). METHODS: This was a cross-sectional comparative study using convenience sampling. HIV-positive adults attending a tertiary referral clinic over a 2-week period were screened for HIV-SN using the AIDS Clinical Trials Group screening tool. HIV-SN was defined as present if the patient had both neuropathic symptoms and abnormal signs. Demographic, clinical, laboratory and treatment data were considered as possible risk factors for HIV-SN, and results were compared with data obtained in the same clinic in 1993 and 2001. RESULTS: One hundred patients were screened. The prevalence of HIV-SN was 42%, which was unchanged since 2001 (44%) despite a significant reduction in the use of dNRTIs. HIV-SN remained much more common than in 1993 (42% vs 13%; P<0.0001). The only independent associations with HIV-SN in 2006 were increasing patient age and a history of exposure to either stavudine or indinavir. This compares with 1993 when neuropathy was increased in those with Mycobacterium avium complex infection, and 2001 when patient age and use of stavudine and didanosine were the independent associations with HIV-SN in this clinic. CONCLUSIONS: HIV-SN remained common among ambulatory patients in 2006 (42% prevalence) despite a significant reduction in the use of dNRTIs. In addition to patient age and stavudine exposure, indinavir use may be a risk factor for HIV-SN.

A randomised controlled trial of omega-3 fatty acid supplementation for the treatment of hypertriglyceridemia in HIV-infected males on highly active antiretroviral therapy.

BACKGROUND: Hypertriglyceridaemia is a recognised metabolic abnormality in HIV-infected people, increasing in severity in people treated with highly active antiretroviral therapy (HAART). An alternative treatment for hypertriglyceridaemia in non-HIV-infected populations is omega-3 fatty acid supplementation. This study aimed to compare the effectiveness of omega-3 fatty acid supplementation and placebo in lowering fasting triglyceride levels in HIV-infected patients on HAART. METHODS: A placebo-controlled, randomised, double-blind trial in participants on stable HAART with fasting triglycerides of >3.5 mm to 10.0 mm using 9 g of omega-3 fatty acids versus placebo (olive oil) after a 6-week lead in on dietary therapy. RESULTS: Eleven patients were enrolled. The mean triglyceride level for the population decreased from 5.02 mm at baseline to 4.44 mm (-11.6%) after dietary intervention and 3.37 mm (-32.9%) after the 8-week treatment period. In the omega-3 fatty acid arm of the study, triglycerides fell from 5.34 mm to 5.02 mm (-6%) after dietary intervention and to 2.30 mm (-56.9%) after the treatment period. In the placebo arm of the study, triglycerides fell from 4.77 mm to 4.05 mm (-15.1%) after dietary intervention and to 4.08 mm (-14.5%) after the treatment period. Using the random effects model, a statistically significant effect on triglycerides of omega-3 fatty acid versus placebo was found (chi(2) = 6.04, P = 0.0487). The estimated difference between groups for change in mean triglycerides over 8 weeks was -2.32 mm (95% CI -4.52, -0.12 mm). CONCLUSIONS: Omega-3 fatty acids are likely to be an effective treatment for hypertriglyceridaemia in HIV-infected males on HAART.

Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial.

BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462. FINDINGS: We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262-316) for NFV, and 274x10(6) cells per L (231-291) for EFV/NFV (p=0.1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0.005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0.0001) and to a treatment modifying adverse event (p=0.04) than those in the other groups. INTERPRETATION: Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen.

Cohort analysis of two multidisciplined adherence intervention programmes for patients on antiretroviral therapy.

The aim was to analyse data from two randomized controlled trials (RCTs) to determine if an adherence intervention programme for antiretroviral therapy (ART) resulted in a reduction in viral load. A cohort analysis of pre- and post-intervention viral loads and CD4 counts using paired analysis was undertaken on participants who received the intervention programme. Analysis was also undertaken on a control group. The intervention participants had an increase in mean CD4 count (450-478, P = 0.26), and a decline in log viral load (2.48-2.36, P = 0.056). The control group had a decline in mean CD4 counts (596-570, P = 0.53), and an increase in log viral load (2.09-2.11, P = 0.78). The use of an adherence intervention programme is associated with a decrease in mean viral load, which is in contrast to the control group that demonstrated an increase in viral load over time.

Increased health care utilization and increased antiretroviral use in HIV-infected individuals with mental health disorders.

OBJECTIVES: The aims of the study were to describe the prevalence and associations of mental health disorder (MHD) among a cohort of HIV-infected patients attending the Victorian HIV/AIDS Service between 1984 and 2000, and to examine whether antiretroviral therapy use or mortality was influenced by MHD (defined as a record of service provision by psychiatric services on the Victorian Psychiatric Case Register). It was hypothesized that HIV-positive individuals with MHD would have poorer treatment outcomes, reduced responses to highly active antiretroviral therapy (HAART) and increased mortality compared with those without MHD. METHODS: This is a retrospective cohort of 2981 individuals (73% of the Victorian population diagnosed with HIV infection) captured on an HIV database which was electronically matched with the public Victorian Psychiatric Case Register (VPCR) (accounting for 95% of public system psychiatry service provision). The prevalence, dates and recorded specifics of mental health disorders at the time of the electronic match on 1 June 2000 are described. The association with recorded MHD, gender, age, AIDS illness, HIV exposure category, duration and type of antiviral therapy, treatment era (prior to 1986, post-1987 and pre-HAART, and post-HAART) on hospitalization and mortality at 1 September 2001 was assessed. RESULTS: Five hundred and twenty-five individuals (17.6% of the Victorian HIV-positive population) were recorded with MHD, most frequently coded as attributable to substance dependence/abuse or affective disorder. MHD was diagnosed prior to HIV in 33% and, of those diagnosed after HIV, 93.8% were recorded more than 1 year after the HIV diagnosis. Schizophrenia was recorded in 6% of the population with MHD. Hospitalizations for both psychiatric and nonpsychiatric illness were more frequent in those with MHD (relative risk 5.4; 95% confidence interval 3.7, 8.2). The total number of antiretrovirals used (median 6.4 agents vs 5.5 agents) was greater in those with MHD. When adjusted for antiretroviral treatment era, HIV exposure category, CD4 cell count and antiretroviral therapy, survival was not affected by MHD. CONCLUSIONS: MHD is frequent in this population with HIV infection and is associated with increased healthcare utilization but not with reduced survival.

Depression and neurocognitive performance in individuals with HIV/AIDS: 2-year follow-up.

OBJECTIVES: The aims of this study were to follow a cohort of HIV-infected individuals for 2 years to assess changes in depression and neuropsychological performance over time, to explore the relationship between depression, HIV illness and neuropsychological performance, and to examine the natural history of the effect of highly active antiretroviral therapy (HAART) on depression and neurocognitive performance. METHODS: HIV-seropositive out-patients were assessed at baseline and at 2-year follow-up. At each assessment, patients were assessed for depression [using the Beck Depression Inventory (BDI) and Structured Clinical Interview (SCID-CV)] and completed a battery of neuropsychological tests including the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Hopkins HIV Dementia Scale (HDS). RESULTS: At baseline, 34.8% scored > or =14 on the BDI [> or =14 suggests depressive symptoms (DS)]. The SCID-CV revealed that 27% of participants met the criteria for current mood disorder. Seven per cent of the participants' scores on the HDS indicated HIV-associated cognitive changes. Eighty participants were re-tested at 2-year follow-up and were split into two groups based on BDI scores at baseline. CANTAB results revealed that the cohort were significantly impaired on nine of 10 measures compared with age-matched normative data. Neurocognitive performance significantly improved for participants with no DS at baseline, whereas participants with DS at baseline did not show as much improvement. Multivariate analysis revealed that 40% of the change in cognitive performance was attributable to the variables age, AIDS and HAART regimen. CONCLUSION: These results suggest a significant decline in depression scores and an improvement in several neurocognitive domains over time, with a relationship between HIV illness, HAART, symptoms of depression and neurocognitive performance.

Breast milk pasteurisation in developed countries to reduce HIV transmission. Do the benefits outweigh the risks?

BACKGROUND: Transmission of HIV through breastfeeding is well documented. The World Health Organisation advise HIV-infected women in developed countries to use alternatives to breastfeeding together with highly active antiretroviral therapy and optimal management of delivery to prevent transmission of HIV to their infant. CASE REPORT: We present the case of an HIV-infected woman electing to exclusively breastfeed for six months and applying milk pasteurisation techniques without transmission to her infant. Two paired samples of her breast milk were tested for HIV RNA prior to and after pasteurisation. The first pair of specimens reported no change in HIV RNA copy number, the second pair of specimens reported an increase in copy number. DISCUSSION: This technique, the evidence for HIV inactivation and the effects pasteurisation has on nutritional and immunological components of breast milk are discussed. CONCLUSION: In conclusion, we believe there is currently insufficient data to recommend this technique either as a safe alternative to formula feeding in resource-rich countries or as a method for providing intact immunological components of breast milk to the infant.

Multidisciplinary HIV adherence intervention: a randomized study.

Maintaining greater than 95% adherence to antiretroviral medication is necessary in order to have the greatest therapeutic impact on HIV infection. Furthermore, evidence suggests that adherence rates of between 70% and 89% are significantly associated with viral rebound and the development of drug resistance. Adherence rates at and above the 95% level are difficult for patients to achieve and maintain. Our aim was to determine if an adherence intervention could improve adherence among patients attending an ambulatory care clinic at a large public hospital. The intervention was delivered by a multidisciplinary team of health care professionals and consisted of education coupled with the provision of devices designed to assist patient memory and adherence. A crucial component of the intervention consisted of the identification of patient specific barriers to adherence and the development of strategies to circumvent these problems. Adherence was assessed using patient self-report over the past 4, 7, and 28 days and by calculation of the Morisky score. The study was conducted as a randomised controlled trial using the stepped wedge design with a total of 68 subjects randomised to receive the intervention over a 20-week period. Adherence before and after the intervention formed the analysis. There was a significant decrease in the number of missed doses over the past 4 (1.9 to 1.0, p < 0.001), 7 (3.0 to 1.8, p < 0.001) and 28 (7.4 to 4.2, p < 0.001) days and a decrease in the Morisky score, indicating an improvement in medication taking behaviour (1.3 to 0.5 p < 0.001).

Randomized trial of an adherence programme for clients with HIV.

Our aim was to determine if a comprehensive adherence package improved self reported adherence to antiretroviral therapy. The adherence package included an education programme, individualized planning of regimens, and the opportunity for a patient to choose from a number of adherence aids and reminder devices. A randomized step wedge design was used. Forty-three individuals were randomized to begin the intervention over a five-month period. There was a substantial fall in the number of missed doses reported for the last four days (0.76 to 0.38, P =0.03) and last seven days (1.5 to 0.74, P =0.005) but not for the last 28 days (2.5 to 2.5, P =0.63). There was no statistical difference in the viral load or CD4 lymphocyte count in the period before or after the intervention. The Morisky score during the pre and post intervention periods was significantly different (P =0.006), 2.9 (SD 0.9) and 3.3 (SD 0.8) respectively. This adherence package improved self reported adherence during the last four and seven days.

Adherence to antiretroviral therapy: are we doing enough?

Adherence to antiretroviral therapy is a powerful predictor of response to therapy. For optimal antiretroviral therapy response, individuals need to take more than 95% of their prescribed medication. The most widely used method for measuring adherence is self-report of the number of missed doses and this should be done at every clinic visit. There are several well-recognized predictors of poor adherence, such as illicit drug use, depression, limited knowledge or ambivalence about starting treatment. Adherence can be improved by addressing these issues or through other means such as pill boxes or electronic reminders.

Successful control of disseminated Scedosporium prolificans infection with a combination of voriconazole and terbinafine.

Disseminated Scedosporium prolificans infections are almost uniformly fatal because of their resistance to antifungal agents. Recently, synergy between triazoles and terbinafine has been demonstrated against Scedosporium prolificans in vitro. Reported here is a patient who developed disseminated Scedosporium prolificans infection following bone marrow transplantation and who was successfully treated with a combination of voriconazole and terbinafine in addition to aggressive surgical debridement. Antifungal synergy testing and combination therapy should be considered in cases of disseminated infection with Scedosporium prolificans.

The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definition.

OBJECTIVES: This study's objective was to determine the prevalence of body shape changes and metabolic abnormalities in an ambulant population with HIV infection. Three different definitions of lipodystrophy were used to assess these changes. Patients' anthropometric measures and dual-energy X-ray absorptiometry (DEXA) scans were compared in order to estimate fat distribution in this population. We sought to evaluate potential predictors for lipodystrophy according to each of the three definitions. METHODS: We performed a cross-sectional study in the outpatient clinic of a tertiary referral hospital in Melbourne, Australia. We enrolled a total of 167 HIV-infected ambulatory patients over 3 months in mid-1998. Data on 159 males, 149 of whom were receiving triple combination antiretroviral therapy, were evaluated. Anthropometric measures, clinical examination, self-report of body shape changes, biochemical measures and DEXA scan were used to assess lipodystrophy and risk factors for cardiovascular disease. Patients described body shape changes in the face, trunk, arms and legs. Laboratory parameters measured included fasting triglyceride (TG), cholesterol, high-density lipoproteins (HDL), glucose, insulin, CD4 cell count and plasma HIV RNA. Current and past antiretroviral therapies were ascertained. RESULTS: According to one proposed Australian national definition of lipodystrophy (LDNC), the prevalence of lipodystrophy in this population was 65%. This definition included an objective assessment with major and minor criteria. Patient-defined lipodystrophy (LDP), which involved a subjective assessment of thinning arms and legs and central adiposity, occurred in 19%. Patient-defined lipoatrophy (LAP), which involved a subjective assessment of thinning arms and legs without central adiposity, occurred in 21.3%. No change in body habitus was noted by 37% of the cohort. Hypercholesterolaemia was recorded in 44%, hypertriglyceridaemia in 52% and elevated insulin levels in 23%. Anthropometry was predictive of the per cent total body fat recorded by DEXA scan, but produced consistently lower values. In multivariate analysis, LDP and LAP were significantly associated with stavudine (d4T) use, while LAP was also associated with zidovudine (ZDV) treatment. There were no treatment associations with LDNC. Protease inhibitor (PI) exposure was associated with metabolic changes but not patient perceived body shape changes, while d4T and ZDV exposure was associated with increased triglycerides and reduced peripheral fat stores. CONCLUSIONS: The prevalence of body shape changes in a single population varied depending on the definition applied. The LDNC definition overestimated body shape abnormalities in comparison with patient perception. LAP was associated with significantly lower fat stores measured by anthropometry and DEXA scan than those identified under the LDNC definition. In contrast to LDNC, LAP was associated with d4T exposure, nucleoside reverse transcriptase inhibitor (NRTI) and ZDV duration of use, but not PI use. Until a consensus definition for lipodystrophy is developed, including agreement on objective measurement and thresholds for abnormality, careful description of the individual components of the syndrome is required to enable cohort comparisons so that predictors of the syndrome can be assessed more accurately and outcome studies made feasible.

Quantification of mitochondrial DNA in peripheral blood mononuclear cells and subcutaneous fat using real-time polymerase chain reaction.

BACKGROUND: With decreased rates of HIV mortality and disease progression attributable to treatment with nucleoside analogue reverse transcriptase inhibitors (NRTIs), attention has now become focused on the toxicities of these forms of treatment. It is believed NRTIs cause a decrease in mitochondrial DNA (mtDNA) synthesis due to their inhibition of DNA polymerase gamma. This hypothesis is supported by in vitro data from muscle biopsies and human lymphoblastic cell lines. The resulting mitochondrial toxicity is thought to manifest itself in a variety of clinical symptoms including fatigue, fat wasting and peripheral neuropathy. A non-invasive test of mitochondrial toxicity is needed to assess toxicity and optimise HIV treatment strategies. Peripheral blood mononuclear cells (PBMC) and subcutaneous fat could be ideal and accessible sources of mtDNA for examining toxicity. OBJECTIVES: The objectives of this study were (a) to develop an assay to quantify the mtDNA copy number of PBMC and obtain reproducible results and (b) to establish the utility of subcutaneous fat as a source of mtDNA for quantification. STUDY DESIGN: PBMC were isolated from blood by centrifugation over Ficoll-Paque and subcutaneous fat was obtained from two 3 mm punch skin biopsies. Following DNA extraction, the mtDNA copy number in each sample was quantified by real-time polymerase chain reaction (PCR). RESULTS: The real-time PCR assay was found to generate consistent and reproducible results with replicates of samples undertaken within the same run, and in two or more different runs, having a mean coefficient of variation of 11.3 and 17.2%, respectively. PBMC and subcutaneous fat contained 409+/-148 and 2042+/-391 copies of mtDNA per cell, respectively. CONCLUSIONS: From the work carried out it can be concluded that firstly, the real-time PCR assay generates consistent and reproducible results, and secondly that mtDNA can be extracted and quantified from PBMC and subcutaneous fat.

Does plasma HIV RNA predict outcome in a cohort of treated HIV-infected individuals followed over 3 years?

BACKGROUND: Despite reductions in AIDS illness and mortality, it is increasingly apparent that a significant proportion of individuals treated with combination antiretroviral (cARV) therapy have continuing or recrudescent HIV RNA in plasma. The predictive value of plasma HIV RNA in treated individual remains uncertain and rates of and risk factors for adverse outcomes such as hospitalisation, opportunistic infections and deaths are needed. OBJECTIVES: The objectives of this study were to establish a retrospective cohort of individuals treated with cARVs, to assess factors associated with detectable HIV RNA and to determine rates of and risk factors for hospitalisation, opportunistic infection and mortality over 3 years of follow-up. STUDY DESIGN: All individuals treated at The Alfred Hospital, Melbourne, Victoria between January and June 1997 who had had plasma HIV RNA measured were included in the retrospective cohort. Clinical, virological and hospitalisation data were recorded and validated by cross-reference with electronically stored laboratory, hospital activity and state notification databases. Outcome was assessed at October 2000. RESULTS: Amongst the 555 individuals tested, 438 (60.7%) had detectable (>500 copies/ml) HIV RNA (bDNA assay, version 2) at baseline. The overall mortality rate was 5.5 per 100 person years; the AIDS rate 1.99 per 100 person years and hospitalisation rate 16.4 per 100 person years. Risk factors for death in this population identified by univariate analysis were HIV RNA concentration at baseline and at follow-up October 2000, nadir and most recent CD4 lymphocyte number, not receiving cARV as initial treatment, total number of ARV agents and number of changes in ARV per year, developing AIDS and being hospitalised during follow-up. In a multivariate model, the most recent CD4 lymphocyte number, the number of different ARVs per year and having more than one hospitalisation remained predictive of death. CONCLUSIONS: HIV RNA remained detectable in the majority (60.7%) of this treatment-experienced population over 3 years, yet mortality rate remained relatively low at 5.5 per 100 person years. Factors associated with death were immunological (CD4 lymphocyte number) and treatment related (numbers of changes of ARV and hospitalisation) rather than virological (HIV RNA) in this cohort. We believe hospitalisation rates may be a useful marker of HIV disease in cARV treated populations and may identify groups at risk of poorer outcome and in need of intervention.