John Chuah

HIV protease inhibitor substitution in patients with lipodystrophy : a randomized, controlled, open-label, multicentre study

BackgroundLipodystrophy, dyslipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. The aims of this study were to determine if these are reversible with continued HIV suppression following protease inhibitor substitution. MethodsEighty-one HIV protease inhibitor recipients (78 male; mean antiretroviral therapy, 55 months) with predominant peripheral lipoatrophy, HIV RNA < 400 copies/ml plasma for at least the preceding 6 months, and no prior abacavir, non-nucleoside analogue or adefovir therapy were randomized 3 : 2 to continue nucleoside analogues and substitute protease inhibitor(s) with abacavir, nevirapine, adefovir and hydroxyurea (n = 49) or to continue all therapy (n = 32) with an option to switch at week 24. The primary endpoints were total body fat and HIV RNA at week 24. Other assessments were regimen safety, regional body composition, metabolic parameters, quality of life, and CD4 T-lymphocyte counts to week 48. ResultsThere was a greater decline in total body fat in the switch group than in the continue group (−1.6 and −0.4 kg, respectively at week 24;P = 0.006). This comprised greater declines in limb and subcutaneous abdominal fat, and in intra-abdominal fat of patients with moderate or severe abdominal fat accumulation. Viral suppression was similar, despite 18 (37%) switch group patients ceasing at least one study drug by week 24 because of adverse events. Total cholesterol and triglycerides declined more in the switch group (both P < 0.002). High density lipoprotein cholesterol increased significantly in both groups at week 48 (P < 0.02). There was no change for any glycaemic parameter. ConclusionsIn predominantly lipoatrophic patients, switching from HIV protease inhibitor therapy lead to improved lipids and less intra-abdominal fat, but also to less peripheral fat, and had minimal effect on insulin resistance. Virological control in these heavily pretreated patients was unaffected, despite frequent switch drug cessations.

The TREAT Asia HIV Observational Database: baseline and retrospective data.

Background:Relatively little is known regarding HIV disease natural history and response to antiretroviral treatments among Asian people infected with HIV. The Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia) HIV Observational Database (TAHOD) is a recently established collaborative observational cohort study that aims to assess HIV disease natural history in treated and untreated patients in the Asia-Pacific region. Methods:Observational data are collected on HIV-infected patients from 11 sites in the Asia-Pacific region. Data are centrally aggregated for analyses, with the first baseline and retrospective data transferred in September 2003. Retrospective data were analyzed to assess the response to highly active antiretroviral treatment (HAART) over a 6-month period in terms of changes in CD4 count and proportions of patients achieving an undetectable HIV viral load (<400 copies/mL). Results:By the end of May 2004, 1887 patients had been recruited to the TAHOD. Seventy-two percent of patients were male, with median age 36 years. Seventy-eight percent of patients reported HIV infection through heterosexual contact. Forty-three percent of patients had a previous AIDS diagnosis, of whom 55% had tuberculosis. The mean 6-month CD4 count increase was 115 cells/μL (SD = 127) after starting triple-combination therapy. Smaller CD4 count increases were associated with a higher CD4 count before starting treatment, prior treatment with monotherapy or double therapy, and treatment with a HAART regimen containing a nucleoside reverse transcriptase inhibitor (NRTI) and/or protease inhibitor (PI) but without a nonnucleoside reverse transcriptase inhibitor (NNRTI). Five hundred and ninety-eight patients started HAART and had a viral load assessment at 6 months, with 69% attaining an undetectable viral load. Older patients, patients not exposed to HIV through heterosexual contact, and patients treated with HAART containing NRTIs and NNRTIs but without PIs were found to be more likely to achieve an undetectable level. Conclusion:Analyses of retrospective data in the TAHOD suggest that the overall response to HAART in Asian populations is similar to that seen in Western countries.

A randomised, open-label comparison of three highly active antiretroviral therapy regimens including two nucleoside analogues and indinavir for previously untreated HIV-1 infection: The OzCombo1 study

BackgroundHighly active antiretroviral therapy (HAART) including two nucleoside analogues and a potent protease inhibitor is standard of care initial therapy for HIV-infected adults. The best-tolerated and most potent initial HAART regimen is unknown and was investigated in this study. MethodsOne hundred and nine HIV-infected adults with no prior antiretroviral therapy, and CD4 lymphocyte counts < 500 × 106 cells/l or plasma HIV RNA > 30 000 copies/ml were randomized to zidovudine–lamivudine–indinavir (ZDV–3TC–IDV), stavudine–lamivudine–indinavir (d4T–3TC–IDV) or stavudine–didanosine–indinavir (d4T–ddI–IDV) for 52 weeks. The primary endpoints were plasma HIV RNA and drug-related adverse events. Other assessments were overall safety, adherence and adverse events, CD4 lymphocyte counts, cutaneous delayed type hypersensitivity (DTH) responses and quality of life (Euroqol). ResultsOnly 58% patients had HIV RNA < 50 copies/ml plasma at 12 months, with no significant difference between the three regimes (P  = 0.34). Drug-related adverse events sufficiently severe to warrant drug discontinuation were less common (P  = 0.06) in patients receiving d4T–3TC–IDV (18%) than in those receiving ZDV–3TC–IDV (34%) or d4T–ddI–IDV (41%). The percentages of patients who remained on their assigned therapy with plasma HIV RNA < 50 copies/ml at 52 weeks were 60% with d4T–3TC–IDV, 53% with ZDV–3TC–IDV and 35% with d4T–ddI–IDV. Virological failure at 52 weeks was more likely in those whose adherence was estimated to be < 100% in the first 4 weeks of therapy (P  = 0.02), but not in those who developed grade 3 or 4 drug-related adverse events. At 52 weeks, the mean CD4 lymphocyte count increase was 200 × 106 cells/l with only 7% of patients having counts lower than at baseline; DTH responses improved but remained clinically impaired in most patients. Quality of life improved significantly in all groups. ConclusionsInitial HAART regimens including IDV failed to suppress plasma HIV RNA to < 50 copies/ml in > 40% patients after only 12 months of therapy although there was significant overall improvement immunologically and in quality of life. The type of dual nucleoside combination used was less important in predicting virological failure than was imperfect adherence early in therapy. Consideration should be given to modifying a HAART regimen relatively early in non-adherent patients.

Inhibition of Telomerase Activity by Human Immunodeficiency Virus (HIV) Nucleos(t)ide Reverse Transcriptase Inhibitors: A Potential Factor Contributing to HIV-Associated Accelerated Aging

BACKGROUND Human immunodeficiency virus (HIV)-infected patients on combination active antiretroviral therapy (cART) are at increased risk of age-related complications. We hypothesized that nucleos(t)ide reverse transcriptase inhibitors (NRTI) may contribute to accelerated aging in HIV-infected individuals on cART via inhibition of telomerase activity. METHODS Telomerase activity and telomere length (TL) were measured by quantitative polymerase chain reaction in vitro in activated peripheral blood mononuclear cells (PBMCs) cultured with NRTI and ex vivo in PBMCs from uninfected patients exposed to NRTI and from HIV-infected patients on NRTI-containing cART. RESULTS Lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir significantly inhibited telomerase activity in activated PBMCs in vitro. Tenofovir was the most potent inhibitor of telomerase activity and caused greatest shortening of TL in vitro at the therapeutic concentration of 0.3 μM. PBMCs from HIV-infected patients receiving NRTI-containing cART (n = 39) had significantly lower telomerase activity than HIV-uninfected patients (n = 47; P = .011) and HIV-infected patients receiving non-NRTI-containing cART (n = 11; P < .001). TL was significantly inversely associated with age (P = .009) and the total duration on any NRTI (P = .01). CONCLUSIONS NRTIs and, specifically tenofovir at therapeutic concentrations, inhibit telomerase activity leading to accelerated shortening of TL in activated PBMCs. The relationship between NRTI, reduced telomerase activity, and accelerated aging requires further investigation in HIV-infected individuals on cART.

Experience with the use of a first-line regimen of stavudine, lamivudine and nevirapine in patients in the TREAT Asia HIV observational Database

The antiretroviral treatment (ART) combination of stavudine, lamivudine and nevirapine (d4T/3TC/NVP) is the most frequently used initial regimen in many Asian countries. There are few data on the outcome of this treatment in clinic cohorts in this region.

A randomized, multicenter, open-label study of poly-L-lactic acid for HIV-1 facial lipoatrophy.

Background:Facial lipoatrophy can stigmatize and can reduce quality of life, self esteem, and antiretroviral adherence. Poly-L-lactic acid (PLA) injections seem safe and effective, but no randomized study has included objective endpoints. Methods:HIV-positive adults with moderate/severe facial lipoatrophy were randomized to 4 open-label PLA treatments administered every 2 weeks from week 0 (immediate group, n = 51) or after week 24 (deferred group, n = 50). The primary endpoint was mean change in facial soft tissue volume (FSTV), as assessed by spiral computed tomography. Analyses were by intention to treat. Results:At week 24, mean changes in FSTV were 0 cm3 in the intermediate group and −10 cm3 in the deferred group (between-group difference of 10 [95% confidence interval (CI): −7 to 28] cm3; P = 0.24). The immediate group had a greater mean change in soft tissue depth at the maxilla (2.2 mm [95% CI: 1.6 to 2.9]; P < 0.0001) and base of the nasal septum (1.0 mm [95% CI: 0.3 to 1.6]; P = 0.003) levels. PLA did not have an impact on peripheral fat mass, viral load, or antiretroviral adherence. Patient and physician subjectively assessed facial lipoatrophy severity (P < 0.0001), 2 of 8 Short Form-36 Health Survey and 2 of 5 Multidimensional Body-Self Relations Questionnaire-Appearance Scales, scores improved significantly. The median duration of treatment-related adverse events was 2 (interquartile range: 1 to 3) days. Conclusions:PLA did not increase FSTV, although tissue thickness in injection planes increased modestly, an improvement observed by patients. PLA was safe and well tolerated. Facial lipoatrophy severity and some quality-of-life domains improved.

Long-Term Patterns in CD4 Response Are Determined by an Interaction Between Baseline CD4 Cell Count, Viral Load, and Time: The Asia Pacific HIV Observational Database (APHOD)

Background:Random effects models were used to explore how the shape of CD4 cell count responses after commencing combination antiretroviral therapy (cART) develop over time and, in particular, the role of baseline and follow-up covariates. Methods:Patients in Asia Pacific HIV Observational Database who first commenced cART after January 1, 1997, and who had a baseline CD4 cell count and viral load measure and at least 1 follow-up measure between 6 and 24 months, were included. CD4 cell counts were determined at every 6-month period after the commencement of cART for up to 6 years. Results:A total of 1638 patients fulfilled the inclusion criteria with a median follow-up time of 58 months. Lower post-cART mean CD4 cell counts were found to be associated with increasing age (P < 0.001), pre-cART hepatitis C coinfection (P = 0.038), prior AIDS (P = 0.019), baseline viral load ≤100,000 copies per milliliter (P < 0.001), and the Asia Pacific region compared with Australia (P = 0.005). A highly significant 3-way interaction between the effects of time, baseline CD4 cell count, and post-cART viral burden (P < 0.0001) was demonstrated. Higher long-term mean CD4 cell counts were associated with lower baseline CD4 cell count and consistently undetectable viral loads. Among patients with consistently detectable viral load, CD4 cell counts seemed to converge for all baseline CD4 levels. Conclusions:Our analyses suggest that the long-term shape of post-cART CD4 cell count changes depends only on a 3-way interaction between baseline CD4 cell count, viral load response, and time.

Trends in detectable viral load by calendar year in the Australian HIV observational database

BackgroundRecent papers have suggested that expanded combination antiretroviral treatment (cART) through lower viral load may be a strategy to reduce HIV transmission at a population level. We assessed calendar trends in detectable viral load in patients recruited to the Australian HIV Observational Database who were receiving cART.MethodsPatients were included in analyses if they had started cART (defined as three or more antiretrovirals) and had at least one viral load assessment after 1 January 1997. We analyzed detectable viral load (>400 copies/ml) in the first and second six months of each calendar year while receiving cART. Repeated measures logistic regression methods were used to account for within and between patient variability. Rates of detectable viral load were predicted allowing for patients lost to follow up.ResultsAnalyses were based on 2439 patients and 31,339 viral load assessments between 1 January 1997 and 31 March 2009. Observed detectable viral load in patients receiving cART declined to 5.3% in the first half of 2009. Predicted detectable viral load based on multivariate models, allowing for patient loss to follow up, also declined over time, but at higher levels, to 13.8% in 2009.ConclusionsPredicted detectable viral load in Australian HIV Observational Database patients receiving cART declined over calendar time, albeit at higher levels than observed. However, over this period, HIV diagnoses and estimated HIV incidence increased in Australia.

Trends in antiretroviral treatment use and treatment response in three Australian states in the first decade of combination antiretroviral treatment

OBJECTIVES To determine if there were any differences in antiretroviral treatment (ART) use across the three eastern states of Australia, New South Wales (NSW), Victoria and Queensland, during the period 1997 to 2006. METHODS We used data from a clinic-based cohort, the Australian HIV Observational Database (AHOD), to determine the proportion of HIV-infected patients on ART in selected clinics in each state and the proportion of treated patients with an undetectable viral load. Data from the national Highly Specialised Drugs program and AHOD were used to estimate total numbers of individuals on ART and the proportion of individuals living with HIV on ART nationally and by state. Data from the HIV Futures Survey and the Gay Community Periodic Survey were used to determine the proportion of community-based men who have sex with men on ART. The proportion of patients with primary HIV infection (PHI) who commenced ART within 1 year of diagnosis was obtained from the Acute Infection and Early Disease Research Program (AIEDRP) CORE01 protocol and Primary HIV and Early Disease Research: Australian Cohort (PHAEDRA) cohorts. RESULTS We estimated that the numbers of individuals on ART increased from 3181 to 4553 in NSW, 1309 to 1926 in Victoria and 809 to 1615 in Queensland between 2000 and 2006. However, these numbers may reflect a lower proportion of individuals living with HIV on ART in NSW compared with the other states (37% compared with 49 and 55% in 2000). We found similar proportions of HIV-positive men who have sex with men participants were on ART in all three states over the study period in the clinic-based AHOD cohort (81-92%) and two large, community-based surveys in Australia (69-85% and 49-83%). Similar proportions of treated patients had an undetectable viral load across the three states, with a consistently increasing trend over time observed in all states. We found that more PHI patients commenced treatment in the first year following HIV diagnosis in NSW compared with Victoria; however, the sample size was very small. CONCLUSIONS For the most part, patterns of ART use were similar across NSW, Victoria and Queensland using a range of available data from cohort studies, community surveys and national prescription databases in Australia. However, there may be a lower proportion of individuals living with HIV on ART in NSW compared with the other states, and there is some indication of a more aggressive treatment approach with PHI patients in NSW compared with Victoria.

Poor baseline immune function predicts an incomplete immune response to combination antiretroviral treatment despite sustained viral suppression.

Objectives:To determine the prevalence and predictors of an incomplete immune response in patients with sustained viral suppression after starting their first or second combination antiretroviral treatment (cART) regimen. Methods:All patients were recruited to the Australian HIV Observational Database (AHOD) by March 2006. Data were analyzed to assess the prevalence of an incomplete immune response (<350 cells/μL) in the 12-24 months after starting the first or second cART regimen. Factors associated with an incomplete immune response were assessed using logistic regression and time to AIDS/death was assessed using survival analysis. Results:Of the 2493 patients recruited to AHOD by March 2006, 590 were eligible for the analysis. Twenty-eight percent of patients with a baseline CD4 count <350 cells per microliter had an incomplete immune response 12-24 months after starting their first or second cART regimen. Lower baseline CD4 count before starting the cART regimen was predictive of an incomplete immune response. There was a nonsignificant trend toward faster AIDS or death in incomplete immune responders. Conclusions:An incomplete immune response in patients with sustained viral suppression is associated with poorer immune function before starting cART. Type of cART or individual antiretroviral drug was not associated with an incomplete immune response.