Incidence of Treatment-Limiting Toxicity with Stavudine-Based Antiretroviral Therapy in Cambodia: A Retrospective Cohort Study

Background: Although stavudine (D4T) remains frequently used in low-income countries in Asia, associated long-term toxicity data are scarce. The aim of this study was to determine the long-term incidence of severe D4T-toxicity (requiring drug substitution) and associated risk factors in HIV-infected Cambodians up to six years on antiretroviral treatment (ART). Methodology/Principal Findings: This is a retrospective analysis of an observational cohort, using data from an ART program with systematic monitoring for D4T-toxicity. Probabilities of time to D4T substitution due to suspected D4T toxicity (treatment-limiting D4T toxicity) were calculated, a risk factor analysis was performed using multivariate Cox regression modelling. Out of 2581 adults initiating a D4T-containing regimen, D4T was replaced in 276 (10.7%) patients for neuropathy, 14 (0.5%) for lactic acidosis and 957 (37.1%) for lipoatrophy. The main early side effect was peripheral neuropathy (7.0 % by 1 year). After the first year, lipoatrophy became predominant, with a cumulative incidence of 56.1 % and 72.4 % by 3 and 6 years respectively. Older age (aHR 1.8; 95%CI: 1.4–2.3) and lower baseline haemoglobin (aHR 1.7; 95%CI: 1.4–2.2) were associated with the occurrence of neuropathy. Being female (aHR 3.8; 95%CI: 1.1–12.5), a higher baseline BMI (aHR 12.6; 95%CI: 3.7–43.1), and TB treatment at ART initiation (aHR 8.6; 95%CI: 2.7–27.5) increased the likelihood of lactic acidosis. Lipoatrophy was positively associated with female gender (aHR 2.3; 95%CI: 2.0–2.6), an older age (aHR 1.3; 95%CI: 1.1–1.4), and a CD4 count,200 cells/mL (aHR 1.3; 95%CI: 1.1–1.5)

Hepatitis B and C co-infection among HIV-infected adults while on antiretroviral treatment: long-term survival, CD4 cell count recovery and antiretroviral toxicity in Cambodia.

BACKGROUND: Despite the high burden, there is a dearth of (long-term) outcome data of hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infected patients receiving antiretroviral treatment (ART) in a clinical setting in resource-constrained settings, particularly from Asia. METHODS: We conducted a retrospective cohort study including all adults initiating standard ART (non-tenofovir-based) between 03/2003 and 09/2012. HBV infection was diagnosed by HBV surface antigen detection. HCV diagnosis relied on antibody detection. The independent effect of HBV and HCV on long-term (≥5 years) ART response in terms of mortality (using Cox regression), severe livertoxicity (using logistic regression) and CD4 count increase (using mixed-effects modelling) was determined. RESULTS: A total of 3089 adults were included (median age: 35 years (interquartile range 30-41); 46% male), of whom 341 (11.0%) were co-infected with HBV and 163 (5.3%) with HCV. Over a median ART follow-up time of 4.3 years, 240 individuals died. Mortality was 1.6 higher for HBV co-infection in adjusted analysis (P = 0.010). After the first year of ART, the independent mortality risk was 3-fold increased in HCV co-infection (P = 0.002). A total of 180 (5.8%) individuals discontinued efavirenz or nevirapine due to severe livertoxicity, with an independently increased risk for HBV (hazard ratio (HR) 2.3; P<0.001) and HCV (HR 2.8; P<0.001). CD4 recovery was lower in both HBV and HCV co-infection but only statistically significant for HBV (P<0.001). DISCUSSION: HBV and HCV co-infection was associated with worse ART outcomes. The effect of early ART initiation and providing effective treatment for hepatitis co-infection should be explored

Cumulative incidence of lipoatrophy.

<p>Kaplan-Meier curve showing the proportion of patients substituting stavudine due to lipoatrophy.</p

Baseline characteristics of adult patients initiating stavudine-containing antiretroviral treatment (N = 2581).

<p>IQR: interquartile range, WHO: world health organization, ART: antiretroviral therapy.</p>a<p>From 2006, stavudine was prescribed as 30 mg bid, irrespective of body weight. Prior to that, 40 mg bid was given for individuals with a body weight >60 kg.</p

Risk factors for severe toxicity related to stavudine.

<p>aHR: adjusted hazard ratio, CI: confidence interval, WHO: world health organization, BMI: body mass index, NNRTI: non-nucleoside reverse transcriptase inhibitor; EFV: efavirenz; NVP: nevirapine; TB: tuberculosis; ART: antiretroviral treatment.</p

Baseline and clinical characteristics of adults initiating ART according to hepatitis B and hepatitis C status in Phnom Penh, Cambodia 2003–2012 (N = 3089).

<p>ART: antiretroviral treatment; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; WHO: world health organization.</p>a<p>There were 3089 individuals included in the study; since there were 12 patients with both HepB and Hep C coinfection, the total adds up to 3101.</p

CD4 evolution after initiation of antiretroviral treatment according to co-infection with hepatitis B virus (upper graph) and hepatitis C virus (lower graph).

<p>CD4 evolution after initiation of antiretroviral treatment according to co-infection with hepatitis B virus (upper graph) and hepatitis C virus (lower graph).</p

Kaplan-Meier graph showing cumulative mortality after initiation of antiretroviral treatment according to co-infection with hepatitis B virus (upper graph) and hepatitis C virus (lower graph).

<p>Kaplan-Meier graph showing cumulative mortality after initiation of antiretroviral treatment according to co-infection with hepatitis B virus (upper graph) and hepatitis C virus (lower graph).</p