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Pretoria, South Africa

Dlamini J.N.,Project Phidisa | Hu Z.,National Institute of Allergy and Infectious Diseases | Somaroo H.,Project Phidisa | Highbarger H.C.,SAIC | And 3 more authors.
Pharmacotherapy | Year: 2011

Study Objective. To evaluate the effect of a previous single dose of nevirapine given to prevent mother-to-child transmission of human immunodeficiency virus (HIV) on virologic and immunologic measures after months of an antiretroviral regimen containing either efavirenz or lopinavir-ritonavir. Design. Retrospective subgroup analysis of data from the Phidisa II trial. Setting. Six South African research clinics. Patients. A total of 394 women with HIV who completed months of combination antiretroviral regimen containing either efavirenz or lopinavirritonavir as part of the Phidisa II trial. Measurements and Main Results. During the screening process for the Phidisa II study, 478 women were asked about previous nevirapine use: 392 women (82%) were nevirapine naïe, and 8 (18%) had received nevirapine. During the study, patients received either an efavirenz-based or lopinavir-ritonavir - based antiretroviral regimen. After months of treatment, virologic (HIV RNA levels) and immunologic (CD4+ cell count) responses were measured. These data were compared between women with or without previous nevirapine exposure, and between women who received efavirenz versus lopinavirritonavir. After months of treatment, 394 women (324 nevirapine naïe, 70 exposed to nevirapine) had follow-up HIV RNA results. Two hundred twenty-seven (70.1%) of the nevirapine-naïe patients and 48 (68.6%) of the nevirapine-exposed patients achieved HIV RNA levels lower than 400 copies/ml (p=0.89), with CD4+ cell count increases of 115.5 and 120.4 cells/mm3, respectively (p=0.67). Among the nevirapine-exposed women, 27 (75%) of 3 efavirenz-treated and 21 (61.8%) of 34 lopinavir-ritonavir-treated patients had HIV RNA levels lower than 400 copies/ml at months (p=0.31). Conclusion. In this retrospective analysis of a small cohort, previous exposure to a single dose of nevirapine did not affect virologic outcomes after months of either an efavirenz-based or lopinavir-ritonavir-based antiretroviral regimen. As efavirenz is one of the first-line combination antiretroviral therapies administered in Africa, it remains an option for women who received single-dose nevirapine.

Ledwaba L.,Project Phidisa | Tavel J.A.,U.S. National Institutes of Health | Khabo P.,Project Phidisa | Maja P.,Project Phidisa | And 9 more authors.
PLoS ONE | Year: 2012

Background: Levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART. Methods: Pre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels. Results: Median baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9-6.7) for hsCRP, 2.6 (95%CI 1.4-4.9) for D-dimer, and 3.8 (95% CI: 1.8-7.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001). Conclusions: Among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted.

Matthews G.V.,University of New South Wales | Manzini P.,Project Phidisa | Hu Z.,National Institute of Allergy and Infectious Diseases | Khabo P.,Project Phidisa | And 7 more authors.
AIDS | Year: 2011

Objective: To examine HIV and hepatitis B virus (HBV)-related outcomes in HIV/HBV-coinfected participants in the PHIDISA II study by use of HBV-active vs. non-HBV-active antiretroviral therapy (ART). Design and Methods: PHIDISA II was a randomized study of ART therapy in HIV-infected adults employing zidovudine along with didanosine, or lamivudine along with stavudine in a factorial 2x2 design. HIV/HBV-coinfected participants by randomization received HBV-active or non-HBV-active ART. The following outcomes of interest were examined: immunological recovery and HIV RNA suppression; hepatic flare; HBV DNA suppression; and mortality. Results: HIV/HBV coinfection was present in 106 of 1771 (6%) of participants. Participants with HIV/HBV coinfection were more likely to be men, and have higher baseline alanine aminotransferase, lower albumin, and lower platelets than those with HIV monoinfection. Median CD4 + cell gain and HIV RNA suppression was similar across all groups. Hepatic flare was observed in 9.4% of coinfected and 0.02% monoinfected participants. HBV DNA suppression (<55IU/ml) at week 48 was observed in only 33% of those on lamivudine vs. 13% in those on no HBV-active drugs (P=0.13). Mortality over follow-up was significantly greater in coinfected (17%) than monoinfected (11%) participants (P=0.04). Conclusion: In summary, the use of lamivudine-containing ART in HIV/HBV participants in PHIDISA II resulted in little additional benefit over that of ART itself and failed to impact on the greater mortality in this group. These data provide strong support for recent guidelines advocating the use of tenofovir in all HIV-HBV-coinfected individuals initiating ART. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Dlamini J.,Project Phidisa | Ledwaba L.,Project Phidisa | Mokwena N.,Project Phidisa | Mokhathi T.,Project Phidisa | And 7 more authors.
Antiviral Therapy | Year: 2011

Background: Lactic acidosis (LA) is a potentially life-threatening complication of antiretroviral (ARV) therapy. Few randomized prospective studies have compared LA between different ARV regimens. Methods: Characterization of cases of LA (serum lactate >5 mmol/l and arterial pH<7.35 or bicarbonate <20 mmol/l) and symptomatic hyperlactataemia (SH; serum lactate >2.2 mmol/l and symptoms) was made in a randomized open-label 2x2 factorial study of stavudine/lamivudine (d4T/3TC)-based versus didanosine/zidovudine-based therapy and lopinavir/ritonavir-based versus efavirenz (EFV)-based therapy in 1,771 HIV-infected adults initiating therapy between 2004 and 2008. Results: The LA incident rate was 3.5/1,000 person-years (95% CI 1.8-5.9), and for combined LA/SH was 11.0/1,000 person-years (95% CI 7.9-14.9). There were two deaths (15% mortality) among 13 LA cases; all 11 survivors experienced symptom resolution and started new ARV regimens. LA cases were more likely to be female (OR 7.19, 95% CI 1.84-40.75; P=0.001) and had a higher body mass index (BMI; P<0.0001) compared with non-cases. There was no increase in LA according to ARV regimen, age or CD4+ T-cell count at randomization. When combined, LA/SH cases (n=41) were more often female (OR 4.76, 95% CI 2.36-10.08; P<0.0001), had increased BMI (P<0.0001), were more likely to be assigned d4T/3TC (OR 3.17, 95% CI 1.50-7.28; P=0.001) and were more likely to be assigned EFV (OR 2.18, 95% CI 1.08-4.61; P=0.026). Conclusions: Female sex and increased BMI were associated with severe LA in this large randomized trial of first-line ARV in South Africa. While female sex, increased BMI and d4T are previously described risk factors for the development of clinically significant lactate elevations, the independent risk associated with EFV is a novel observation warranting further investigation. ©2011 International Medical Press.

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