Although drug side-effects due to antiretroviral therapy (ART) are relatively common in African patients, they are no more likely to be severe than in patients in industrialised countries, and appear chiefly related to the d4T (stavudine, Zerit) component of first-line treatment rather than to nevirapine (Viramune), according to two large studies presented on Wednesday at the Thirteenth Conference on Retroviruses and Opportunistic Infections in Denver.
Two studies investigated the toxicity of ART in African settings. In the first, treatment was provided by a home-based care programme in rural Uganda, and in the second through a clinic located in the Kibera slums of Nairobi, Kenya.
In both settings, the first-line regimen most frequently used was d4T/3TC (lamivudine, Epivir)/nevirapine while a much smaller number of patients used d4T/3TC/efavirenz(Sustiva).
In both studies, neuropathy and rash were by far the most common side-effects. Nevirapine-related hepatitis or hypersensitivity reactions were rarely reported.
Toxicity led to switching single drugs or the ART regimen in some patients (usually just a single drug). The drug most likely to be switched was d4T. Even though toxicity was just as frequently reported at the Kenyan clinic, changes in treatment due to toxicity were much more likely in the Ugandan home-based care programme (21%) than at the Kenyan clinic (5%).
Toxicity In Ugandan home-based care patients study (Forna)
The Ugandan study included 1037 people with symptomatic HIV disease or CD4 cell counts below 250 cells/mm3 who started on ART provided by a home-based AIDS care (HBAC) project in rural Uganda. Home-based care consisted of weekly motorcycle visits to the patients' homes by field officers to deliver drug, provide adherence support and monitor for illness and side-effects. Patients were referred for clinic visits for illness and toxicity. Medical officers evaluated each adverse event and graded its severity.
Of 1037 ART-naive adults, 73% were women, with a median CD4 cell count of 126 cells/mm3 and a median body mass index of 20. One thousand received d4T/3TC/nevirapine and 37 received d4T/3TC/efavirenz.
After 950 patient-years (median 0.94 years/patient) of follow-up, 417 patients (40%) developed 547 clinical toxicities. 325 patients (36%) developed neuropathy (10% grade 3 or 4); 59 (6%) had rash (25 [2%] severe); 17 (2%) a hypersensitivity reaction; 5 (0.5%) acute hepatitis; 4 (0.4%) anaemia; 3 (0.3%) acute pancreatitis; 1 (0.1%) lactic acidosis; 132 (13%) other toxicities (e.g., nausea, vomiting, asthenia, psychiatric disorder).
The vast majority of the 220 drug changes during the follow-up period involved a switch from d4T to AZT (zidovudine, Retrovir) (17% of all treated patients made this change), with 4% of patients switching from nevirapine to efavirenz.
In a Kaplan-Meier analysis, the probability of remaining free from any toxicity at 6, 12, and 18 months was 0.76, 0.59, and 0.47, respectively, while the probability of remaining free from severe toxicities at 6, 12, and 18 months was 0.92, 0.86, and 0.84, respectively.
The probability of remaining on the original regimen without change for toxicity at 6, 12, and 18 months were 0.91, 0.78, and 0.73, respectively.
Toxicity was associated with age greater than 35 years (OR 1.82), and severe toxicity with age greater than 35 years (OR 2.88) and concomitant TB treatment (OR 2.1).
Fatu Foran of the United States Centers for Disease Control's Global AIDS Program said that the study may have under-reported toxicity, since there was no standardised examination for peripheral neuropathy. Also the study did not conduct laboratory monitoring, so cases of hyperlactatemia may have been missed or under-reported (although she noted that symptoms associated with hyperlactatemia such as as thenia and vomiting were considerably less common than peripheral neuropathy).
She ruled out HIV as the cause of the high incidence of peripheral neuropathy, since the study excluded patients with peripheral neuropathy at baseline. However field officers did look for peripheral neuropathy proactively in order to ensure that patients switched treatment before the condition became so severe that it prevented people from walking.
She advised that paying more attention to the risk of toxicity in older patients (>35 years) and those also receiving TB treatment (chiefly isoniazid) may help to reduce the burden of toxicity.
“In resource-limited settings, ART intolerance to a regimen containing d4T and NVP [nevirapine] presents a manageable barrier to care, though more tolerable regimens would be desirable,” she said.
The Kenyan study (Kim)
The Kenyan study involved 283 people with symptomatic HIV disease or CD4 cell count 3 treated at a clinic in the Kibera slums of Nairobi between February 2003 to February 2005. Clinical and lab toxicities were evaluated at scheduled visits, and graded for severity, and patients were managed by clinical officers.
Data were presented on 284 patients (70% women) with a median CD4 cell count of 157 cells/mm3, all but 16 of whom started treatment with d4T/3TC/nevirapine (twelve received d4T/3TC/efavirenz and four received other drugs due to prior exposure)
After 254 patient-years of observation (median 0.9 years per patient), 184 (65%) patients had developd some form of clinical toxicity, 17 (6%) had severe toxicity. 65 (23%) developed neuropathy, which was severe in seven (3%); 58 (20%) had rash, severe in four (1.4%), 16% had nausea, severe In 0.4% of cases, and four cases of clinical hepatitis were reported.
Only two cases of lipodystrophy were observed, one of which was severe.
Kaplan-Meier analysis of time to a first adverse event showed cumulative probabilities of 0.47, 0.26 and 0.17 at 6, 12 and 18 months respectively, and cumulative probabilities of 0.99, 0.95 and 0.89 to a severe adverse event at months 6, 12 and 18.
The liver enzyme AST was evaluated in 233 patients and was normal at baseline in 76% of cases. It subsequently became elevated to grade one in 117 (42%), grade 2 (20%) and to grade 3 or 4 in 3 (1.3%) patients. Kaplan-Meier analysis of time to first grade 1 AST elevation showed cumulative probablities of 0.45, 0.27 and 0.21 at months 6, 12 and 18.
Eight patients changed treatment from nevirapine to efavirenz (4 due to rash, 4 due to hepatitis) and five changed from d4T to AZT (four due to peripheral neuropathy and one due to lipodystrophy).
Andrea Kim of the US Centers for Disease Control Global AIDS Program concluded: “These results indicate that among populations in resource-limited settings, ART tolerance should not represent a significant barrier to care. The rates of adverse events appear to be In a range consistent with those of industrialised countries."
Forna F et al. Early clinical toxicity to nonnucleoside reverse transcriptase Inhibitor-based HAART in a home-based AIDS care program in rural Uganda. 13th Conference on Retroviruses and Opportunistic Infections, Denver, abstract 142, 2006.
Kim A et al. Adverse events in HIV-infected patients receiving ART in a treatment program in a Nairobi slum, Kenya, 2003 to 2005. 13th Conference on Retroviruses and Opportunistic Infections, Denver, abstract 143, 2006.