After two years patients treated with potent antiretroviral therapy in Cambodia have outcomes at least as good as those seen in antiretroviral-treated patients in industrialised countries, according to a study published in the November edition of AIDS. An intent-to-treat analysis showed that 75% of patients had a viral load below 400 copies/ml and that the probability of two-year survival was 85%.
Many resource-limited settings have a limited access to viral load testing and the investigators found that prior treatment with antiretrovirals, low drug levels, CD4 cell count below 350 cells/mm3 and a CD4 cell percentage gain of less than 23% between months twelve and 24 of treatment, were associated with a viral load above 1000 copies/ml after two years.
The feasibility of antiretroviral therapy has been well demonstrated in resource poor settings. Research has shown that adherence to anti-HIV treatment in such settings is as least as good as that seen in western countries. Nevertheless, concerns have been raised about the maintenance of rigorously adherence in the long-term and the effect of side-effects on longer-term adherence and subsequent viral control.
There are limited data regarding medium- and long-term outcomes in patients receiving anti-HIV treatment in resource limited countries. But investigators from Medecins Sans Frontieres and the Cambodian Ministry of Health were able to conduct a cross-sectional study involving patients who had received 24 months of potent anti-HIV therapy by March 2005.
A total of 416 patients were included in the investigators’ analysis with a median age of 34 years. Almost all (96%) were naïve to antiretroviral therapy at baseline. Most of the patients had progressed to advanced HIV disease by the time they started anti-HIV therapy, with 46% having an AIDS diagnosis and median CD4 cell count being 11 cells/mm3. Median body mass index (BMI) on entry to the study was low, with 41% having a BMI below 18kg m2.
First-line treatment consistent of efavirenz, d4T and 3TC, with nevirapine being offered as an alternative NNRTI and AZT in place of d4T. Protease inhibitor therapy, consisting of lopinavir/ritonavir was mainly reserved for second-line therapy.
Three counselling sessions were provided to patients before anti-HIV therapy was started.
Patients were followed for a median of 23.8 months. During this time 53 (13%) died, seven (2%) were lost to follow-up and 1% transferred care to another centre. The remaining 84% were alive and continuing with antiretroviral therapy. The investigators estimated that patients had an 87% probability of being alive after twelve months of antiretroviral therapy and a 85% probability of being alive after 24 months.
Two-thirds of the deaths occurred during the first six months of anti-HIV therapy (median time to death, 3.6 months).
After six months of treatment, the median CD4 cell gain was 101 ells/mm3; the median twelve month gain was 154 cells/mm3, the median 24 month gain being 233 cells/mm3. Even though median baseline CD4 cell count was very low, 75% of patients had a CD4 cell count above 200 cells by month 24.
Twenty-four month viral load data were similarly encouraging with 80% of patients having a viral load below 40 copies/ml and 88% a viral load below 400 copies/ml. Only 4% of patients had a viral load above 30,000 copies/ml, the investigators’ definition of virological failure.
When the investigators performed a rigorous intent-to-treat analysis that treated deaths, loss to follow-up and missing data as treatment failures, they found that 66% of patients had a viral load below 40 copies/ml and 74% a viral load below 400 copies/ml.
Resistance tests were performed on 40 patients with viral loads above 400 copies/ml. These showed that 59% had NRTI-associated resistance, 71% had NNRTI resistance and 26% had no resistance mutations.
Drug level monitoring tests showed that 4% of patients had sub-therapeutic levels of efavirenz and 28% had efavirenz concentrations above 1000ng/ml, a level that has been associated with an increased risk of neuropsychiatric side-effects. Sub-therapeutic levels of nevirapine were found in 4% of patients.
Further analysis showed that 47% of patients with low levels of NNRTIs in their blood had viral load above 1000 copies/ml.
When the investigators looked at the occurrence of side-effects in their cohort, they found that 2% of AZT-treated patients stopped treatment with the drug (for anaemia or neutropenia). Of the patients taking d4T, 32% stopped taking the drug because of neuropathy, lipodystrophy and mitochondrial toxicity. Only 1% of patients taking efavirenz discontinued the drug, the reason being neuropsychiatric toxicity. Three per cent of patients taking nevirapine stopped the drug, the reasons including rash, allergy and liver inflammation.
The patients who stopped AZT did so after a median of 93 days, with the median duration of d4T treatment before discontinuation being 14 months, 22 days for nevirapine and between ten days and two years for efavirenz.
Analysis was then performed to see if it was possible to find factors that predicted a viral load greater than 1000 copies/ml at month. Such analysis is important as access to viral load testing in many resource-imited settings is limited.
The investigators found that previous suboptimal anti-HIV treatment (p = 0.002), low plasma drug concentrations (p = 0.001) and a CD4 cell count below 350 cells/mm3 and a CD4 percentage gain of less than 23% between months twelve and 24 (p = 0.003) were all significantly associated with having a viral load above 1000 copies/ml.
Combining these criteria had a 74% sensitivity, a 75% specificity, a 21% positive predictive value and a 96% negative predictive value. Using these combined criteria, the investigators estimated that they would be able to detect 50% more patients in need of treatment change with a viral load above 1000 copies/ml than current WHO criteria.
“The present analysis of 416 patients performed 24 months after HAART initiation in Cambodia found 75% of treatment successes (patients still followed with a viral load
Ferradini L et al. Positive outcomes of HAART at 24 months in HIV-infected patients in Cambodia. AIDS 21: 2293 – 2301, 2007.