Morbidity and mortality according to latest CD4+ cell count among HIV positive individuals in South Africa who enrolled in project Phidisa.

BACKGROUND: Short-term morbidity and mortality rates for HIV positive soldiers in the South African National Defence Force (SANDF) would inform decisions about deployment and HIV disease management. Risks were determined according to the latest CD4+ cell count and use of antiretroviral therapy (ART) for HIV positive individuals in the SANDF and their dependents. METHODS AND FINDINGS: A total of 7,114 participants were enrolled and followed for mortality over a median of 4.7 years (IQR: 1.9, 7.1 years). For a planned subset (5,976), progression of disease (POD) and grade 4, potentially life-threatening events were also ascertained. CD4+ count and viral load were measured every 3 to 6 months. Poisson regression was used to compare event rates by latest CD4+ count (<50, 50-99, 100-199, 200-349, 350-499, 500+) with a focus on upper three strata, and to estimate relative risks (RRs) (ART/no ART). Median entry CD4+ was 207 cells/mm3. During follow-up over 70% were prescribed ART. Over follow-up 1,226 participants died; rates ranged from 57.6 (< 50 cells) to 0.8 (500+ cells) per 100 person years (py). Compared to those with latest CD4+ 200-349 (2.2/100 py), death rates were significantly lower (p<0.001), as expected, for those with 350-499 (0.9/100 py) and with 500+ cells (0.8/100 py). The composite outcome of death, POD or grade 4 events occurred in 2,302 participants (4,045 events); rates were similar in higher CD4+ count strata (9.4 for 350-499 and 7.9 for 500+ cells) and lower than those with counts 200-349 cells (13.5) (p<0.001). For those with latest CD4+ 350+ cells, 63% of the composite outcomes (680 of 1,074) were grade 4 events. CONCLUSION: Rates of morbidity and mortality are lowest among those with CD4+ count of 350 or higher and rates do not differ for those with counts of 350-499 versus 500+ cells. Grade 4 events are the predominant morbidity for participants with CD4+ counts of 350+ cells.

Genotypic resistance at viral rebound among patients who received lopinavir/ritonavir-based or efavirenz-based first antiretroviral therapy in South Africa.

Nonnucleoside reverse transcriptase inhibitor-drug resistance mutations (DRM) are increasingly reported in Africans failing their first antiretroviral regimen. The Phidisa II trial randomized treatment-naive participants to lopinavir/ritonavir or efavirenz with stavudine + lamivudine or zidovudine + didanosine. We report the prevalence of DRM in subjects who achieved HIV RNA <400 copies per milliliter at 6 months, but subsequently had 2 consecutive HIV RNA >1000 copies per milliliter. Sixty-eight participants fulfilled the inclusion criteria. nonnucleoside reverse transcriptase inhibitor-DRM were found in 17 of 36 (47.2%) efavirenz recipients, and M184V/I mutation in 14 of 40 (35.0%) lamivudine recipients. No protease inhibitor mutation was identified in 38 lopinavir/ritonavir recipients. This is one of the first studies in Africa confirming the paucity of protease inhibitor-associated DRM despite virologic failure.

Tuberculosis risk factors and mortality for HIV-infected persons receiving antiretroviral therapy in South Africa.

OBJECTIVE: To determine important risk factors for and impact of tuberculosis on survival in HIV-infected patients starting antiretroviral therapy (ART) in South Africa. DESIGN: Prospective trial of 1771 HIV-infected patients with either CD4 cell count less than 200 cells/microl or a prior AIDS-defining illness, enrolled in randomized trial of four antiretroviral regimens. METHODS: Data collected from patient records. RESULTS: A history of tuberculosis at study entry was reported by 27% of patients and correlated with poor baseline health status. A history of tuberculosis at baseline was associated with subsequent tuberculosis and death during ART, but was not itself an independent risk factor for poor outcome. Tuberculosis was diagnosed during ART in 14% of patients and was more frequent during the first 3 months. Tuberculosis during therapy was independently associated with increased hazard of other AIDS-defining events and death, regardless of when during ART tuberculosis occurred. ART that consistently suppressed circulating viremia reduced but did not eliminate tuberculosis risk. CONCLUSION: In HIV-infected patients who started ART at low CD4 cell counts, tuberculosis at baseline was a predictor of death, but was not independent of other factors indicating poor baseline health status. Tuberculosis during follow-up was, in contrast, an independent predictor of death even after adjustments for baseline risk factors, including CD4 cell count and viral load. Virologic failure during ART was associated with a 55% increase in risk of tuberculosis. Thus, tuberculosis is a major marker for poor outcome both at baseline and during ART and is not completely eliminated by fully suppressive ART.

Detection of a substantial rate of multidrug-resistant tuberculosis in an HIV-infected population in South Africa by active monitoring of sputum samples.

BACKGROUND: Tuberculosis (TB) coinfection with human immunodeficiency virus (HIV) is a substantial problem in South Africa. There has been a presumption that drug-resistant strains of TB are common in South Africa, but few studies have documented this impression. METHODS: In Phidisa, a joint observational and randomized HIV treatment study for South African National Defence Force members and dependents, an initiative was launched to test subjects (by use of microbiologic TB test) who appeared to be at high risk. We report results for HIV-infected subjects. RESULTS: TB was identified by culture in 116 (19.9%) of 584 patients selected for sputum examination on the basis of suggestive symptoms. Smear was an insensitive technique for confirming the diagnosis: only 33% of culture-positive patients were identified by smear, with a 0.2% false-positive rate. Of the 107 culture-positive individuals with susceptibility testing, 22 (20.6%) were identified to be multidrug resistant (MDR), and 4 (3.7%) were identified to be extensively drug resistant. Culture-positive cases with a history of TB treatment had more than twice the rate of MDR than those without (27.1% vs 11.9%; P = .05). CONCLUSIONS: TB is common in this cohort of HIV-infected patients. Smear was not a sensitive technique for identifying culture-positive cases in this health system. Drug susceptibility testing is essential to proper patient management because MDR was present in 20.6% of culture-positive patients. Better management strategies are needed to reduce the development of MDR TB, because so many of these patients had received prior antituberculous therapy that was presumably not curative.

A nonparametric likelihood test for detecting discordance between two measurements with application to censored viral load determinations.

Patient management frequently involves quantitative evaluation of a patient's attributes. For example, in HIV studies, a high viral load can be a trigger to initiate or modify an antiretroviral therapy. At times, a new method of evaluation may substitute for an established one, provided that the new method does not result in different clinical decisions compared with the old method. Traditional measures of agreement between the two methods are inadequate for deciding if a new method can replace the old. Especially, when the data are censored by a detection limit, estimates of agreement can be biased unless the distribution for the censored data is correctly specified; this is usually not feasible in practice. We propose a nonparametric likelihood test that seamlessly handles censored data. We further show that the proposed test is a generalization of the test on nominal measurement concordance to continuous measurement. An exact permutation procedure is proposed for implementing the test. Our application is an HIV study to determine whether one method of processing plasma samples can safely substitute for the other. The plasma samples are used to determine viral load and a large portion of data are left censored due to a lower detection limit.