Nevirapine-Associated Early Hepatotoxicity: Incidence, Risk Factors, and Associated Mortality in a Primary Care ART Programme in South Africa

BACKGROUND: The majority of antiretroviral treatment programmes in sub-Saharan Africa are scaling up antiretroviral treatment using a fixed dose first-line antiretroviral regimen containing stavudine, lamivudine, and nevirapine. One of the primary concerns with the use of this regimen is nevirapine-associated hepatotoxicity. METHODOLOGY/PRINCIPAL FINDINGS: Study participants were 1809 HIV-infected, antiretroviral naïve adults initiating nevirapine-based antiretroviral therapy between November 2002 and December 2006. The primary outcome was early hepatotoxicity. Secondary outcomes were associations with hepatotoxicity and mortality at six months. The cumulative proportion of early hepatotoxicity ranged from 1.0-2.0% giving an incidence-rate at 102 days of 3.6-7.6 per 100 person-years. Median time to hepatotoxicity was 32 (IQR 28-58) days. At 12 weeks, only 8% of patients had alanine aminotransferase monitoring at all the time-points recommended by national guidelines. No association was found between age, gender, baseline CD4 count, concurrent tuberculosis infection, prior participation in a prevention of mother-to-child-transmission program, or baseline weight and early hepatotoxicity. There was no association between early hepatotoxicity and mortality. CONCLUSIONS: The cumulative proportion of early hepatotoxicity in nevirapine based antiretroviral therapy was low in this resource-constrained setting. Hepatotoxicity was not associated with mortality. Frequent routine monitoring of alanine aminotransferase proved difficult to implement in this public sector primary care programme. Focused monitoring in the first month may be a more cost-effective and pragmatic option in settings with limited resources. Correlation with clinical signs and symptoms may allow future alanine aminotransferase testing to be dictated by clinical criteria

Central nervous system disorders afrer starting antiretroviral therapy in South Africa

Objective: To describe the spectrum of central nervous system (CNS) disease during the first year of antiretroviral therapy (ART), and to determine the contribution of neurological immune reconstitution inflammatory syndrome (IRIS). Design: A prospective observational cohort study conducted over a 12-month period at a public sector referral hospital in South Africa. Methods: HIV seropositive patients who developed new or recurrent neurological or psychiatric symptom(s) or sign(s) within the first year of starting ART were enrolled. We used the number of patients starting ART in the referral area in the preceding year as the denominator to calculate the incidence of referral for neurological deterioration. Patients with delirium and peripheral neuropathy were excluded. Outcome at six months was recorded. Results: Seventy-five patients were enrolled. The median nadir CD4+ count was 64 cells/μL. 59% of patients were receiving antituberculosis treatment. The incidence of referral for CNS deterioration in the first year of ART was 23.3 cases (95% CI, 18.3–29.2) per 1000 patient years at risk. CNS tuberculosis (n=27, 36%), cryptococcal meningitis (n=18, 24%), intracerebral space occupying lesions (other than tuberculoma) (n=10, 13%) and psychosis (n=9, 12%) were the most frequent diagnoses. Paradoxical neurological IRIS was diagnosed in 21 patients (28%), related to tuberculosis in 16 and cryptococcosis in 5. At 6 months, 23% of patients had died and 20% were lost to follow-up. Conclusion: Opportunistic infections, notably tuberculosis and cryptococcosis, were the most frequent causes for neurological deterioration after starting ART. Neurological IRIS occurred in over a quarter of patients