Salome Charalambous

Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa.

Objective:To assess the performance of WHO clinical and CD4 cell count criteria for antiretroviral treatment (ART) failure among HIV-infected adults in a workplace HIV care programme in South Africa. Design:Cohort study. Methods:We included initially ART-naive participants who remained on first-line therapy and had an evaluable HIV viral load result at the 12-month visit. WHO-defined clinical and CD4 cell count criteria for ART failure were compared against a gold standard of virological failure. Results:Among 324 individuals (97.5% men, median age 40.2, median starting CD4 cell count and viral load 154 cells/μl and 47 503 copies/ml, respectively), 33 (10.2%) had definite or probable virological failure at 12 months, compared with 19 (6.0%) and 40 (12.5%) with WHO-defined CD4 and clinical failure, respectively. CD4 criteria had a sensitivity of 21.2% and a specificity of 95.8% in detecting virological failure, and clinical criteria had sensitivity of 15.2% and specificity of 88.1%. The positive predictive value of CD4 and clinical criteria in detecting virological failure were 36.8 and 12.8%, respectively. Exclusion of weight loss or tuberculosis failed to improve the performance of clinical criteria. Conclusion:WHO clinical and CD4 criteria have poor sensitivity and specificity in detecting virological failure. The low specificities and positive predictive values mean that individuals with adequate virological suppression risk being incorrectly classified as having treatment failure and unnecessarily switched to second-line therapy. Virological failure should be confirmed before switching to second-line therapy.

High-Dose Rifapentine with Moxifloxacin for Pulmonary Tuberculosis

BACKGROUND Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed. METHODS We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals. RESULTS We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4). CONCLUSIONS The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

That is why I stopped the ART: Patients' & providers' perspectives on barriers to and enablers of HIV treatment adherence in a South African workplace programme

BackgroundAs ART programmes in African settings expand beyond the pilot stages, adherence to treatment may become an increasing challenge. This qualitative study examines potential barriers to, and facilitators of, adherence to ART in a workplace programme in South Africa.MethodsWe conducted key informant interviews with 12 participants: six ART patients, five health service providers (HSPs) and one human resources manager.ResultsThe main reported barriers were denial of existence of HIV or of ones own positive status, use of traditional medicines, speaking a different language from the HSP, alcohol use, being away from home, perceived severity of side-effects, feeling better on treatment and long waiting times at the clinic. The key facilitators were social support, belief in the value of treatment, belief in the importance of ones own life to the survival of ones family, and the ability to fit ART into daily life schedules.ConclusionGiven the reported uncertainty about the existence of HIV disease and the use of traditional medicines while on ART, despite a programme emphasising ART counselling, there is a need to find effective ways to support adherence to ART even if the individual does not accept biomedical concepts of HIV disease or decides to use traditional medicines. Additionally, providers should identify ways to minimize barriers in communication with patients with whom they have no common language. Finally, dissatisfaction with clinical services, due to long waiting times, should be addressed.

Hepatotoxicity in an African antiretroviral therapy cohort: The effect of tuberculosis and hepatitis B

Objective:Hepatotoxicity is a significant complication of antiretroviral therapy (ART). We assessed the incidence of and risk factors for hepatotoxicity among HIV-infected individuals on ART in South Africa. Design:We conducted a retrospective cohort study in a workplace HIV care program in South Africa which uses a first-line regimen of efavirenz, zidovudine, and lamivudine and provides routine clinical and laboratory monitoring. Methods:We included subjects with baseline and follow-up alanine transaminase and aspartate aminotransferase tests. Severe hepatotoxicity cases were identified during the first 12 months of ART. Potential risk factors, including concomitant medication use, tuberculosis, and hepatitis B and C, were determined from clinical records, database queries, and serological testing. Associations with hepatotoxicity were investigated using Cox proportional hazards modeling. Results:Of the 868 subjects (94% male, median age 41 years), the median nadir CD4 cell count was 136/μl, 25% received concomitant tuberculosis treatment during ART, and 17% of a randomly selected subset were positive for hepatitis B surface antigen (HBsAg). We identified 7.7 episodes of severe hepatotoxicity per 100 person-years. Tuberculosis treatment increased risk 8.5 fold, positive HBsAg 3.0 fold, and nadir CD4 cells count < 100/μl 1.9 fold. Importantly, the fraction of patients with severe hepatotoxicity on ART (4.6%) was similar to the fraction with liver enzyme elevations > 5 times the upper limit of normal before starting ART (4%). Conclusions:In this African ART cohort, we found a low incidence of and minimal morbidity due to hepatotoxicity. HBsAg and concomitant tuberculosis therapy significantly increased the risk of hepatotoxicity.

Hepatitis B Virus Infection and Response to Antiretroviral Therapy (ART) in a South African ART Program

BACKGROUND Coinfection with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) is common in Africa; however, the impact of HBV infection on the outcomes of antiretroviral therapy programs is unclear. We evaluated the impact of chronic hepatitis B on HIV virologic response, changes in CD4 cell count, hepatotoxicity, and mortality among Africans receiving highly active antiretroviral therapy (HAART). METHODS We conducted a retrospective cohort study involving a workplace HAART program in South Africa. Participants received HAART according to a protocol and were followed up for up to 72 weeks. On the basis of pre-HAART serum assays, patients were classified as being hepatitis B surface antigen (HBsAg) negative, HBsAg positive with a low HBV DNA level (</= 1 x 10(4) copies/mL), and HBsAg positive with a high HBV DNA level (> 1 x 10(4) copies/mL). The relationships between HBV status and HIV RNA suppression, change in CD4 cell count, mortality, and hepatotoxicity were assessed with use of regression techniques. RESULTS Five hundred thirty-seven individuals fulfilled the inclusion criteria; 431 (80.3%) of these patients were HBsAg negative, 60 (11.2%) were HBsAg positive with a low HBV DNA level, and 46 (8.6%) were HBsAg positive with a high HBV DNA level. All groups had similar rates of HIV RNA suppression (P = .61), CD4 cell count increases (P =.75), and mortality (17 total deaths; P=.11) for up to 72 weeks after the initiation of HAART. Baseline transaminase levels were highest in the group with high HBV DNA levels (P=.004). Hepatotoxicity was similar between the HBsAg-negative group and the group with low HBV DNA levels but was higher in the group with high HBV DNA levels (incidence rate ratio, 4.4). CONCLUSIONS We revealed that HBV status does not affect HIV RNA suppression, CD4 cell count response, or mortality during the first 72 weeks of HAART in an African setting. The risk of HBV-associated hepatotoxicity, however, is associated with the baseline HBV DNA level.

Use of traditional medicine by HIV-infected individuals in South Africa in the era of antiretroviral therapy

Abstract As antiretroviral therapy (ART) becomes more available in African countries, the potential for interaction with traditional medicines becomes more important. We carried out a cross-sectional survey among individuals with moderate or advanced HIV disease attending a workplace clinic providing ART in South Africa to determine prevalence of traditional medicine use, source, recommended products and costs. Among 44 clinic attendees (100% male, median age 42 years, 30 taking ART), 37 (84%) reported ever using traditional medicines, 25 obtained from a healer or herbalist, eight from their own fields and four from a pharmacy. Fourteen of the 44 (32%) were currently using traditional medicines, most frequently African potato (9/14) and Aloe vera (3/14). Seven out of 30 persons taking ART (23%) reported currently using traditional medicines. Participants spent £4 – 27 per month on traditional medicines. Traditional medicine use is common among individuals with moderate and advanced HIV disease. Concomitant use with ART has the potential for drug interactions and should be discussed routinely in ART counselling. Further work is warranted to investigate whether commonly used traditional medicines interact with ART in vivo.

Viremia and drug resistance among HIV-1 patients on antiretroviral treatment: a cross-sectional study in Soweto, South Africa

Background:We assessed risk factors for viremia and drug resistance among long-term recipients of antiretroviral therapy (ART) in South Africa. Methods:In 2008, we conducted a cross-sectional study among patients receiving ART for 12 months or more. Genotypic resistance testing was performed on individuals with a viral load higher than 400 RNA copies/ml. Multiple logistic regression analysis was used to assess associations. Results:Of 998 participants, 75% were women with a median age of 41 years. Most (64%) had been on treatment for more than 3 years. The prevalence of viremia was 14% (n = 139): 12% (102/883) on first-line [i.e. nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen] and 33% (37/115) on second-line (i.e. protease inhibitor (PI)-based regimen) ART. Of viremic patients, 78% had drug resistance mutations. For NRTIs, NNRTIs and PIs, the prevalence of mutations was 64, 81 and 2%, respectively, among first-line failures and 29, 54 and 6%, respectively, among second-line failures. M184V/I, K103N and V106A/M were the most common mutations. Significant risk factors associated with viremia on first-line regimen included concurrent tuberculosis treatment [odds ratio (OR) 6.4, 95% confidence interval (CI) 2.2–18.8, P < 0.01] and a recent history of poor adherence (OR 2.7, 1.3–5.6, P = 0.01). Among second-line failures, attending a public clinic (OR 4.6, 95% CI 1.8–11.3, P < 0.01) and not having a refrigerator at home (OR 6.7, 95% CI 1.2–37.5, P = 0.03) were risk factors for virological failure. Conclusion:Risk factors for viral failure were line regimen dependent. Second-line ART recipients had a higher rate of viremia, albeit with infrequent PI drug resistance mutations. Measures to maintain effective virologic suppression should include increased adherence counseling, attention to concomitant tuberculosis treatment and heat-stable formulations of second-line ART regimens.

Viremia, resuppression, and time to resistance in human immunodeficiency virus (HIV) subtype C during first-line antiretroviral therapy in South Africa.

BACKGROUND Episodes of viremia are common in African antiretroviral therapy (ART) programs. We sought to describe viremia, resuppression, and accumulation of resistance during first-line combination ART (cART) in South Africa. METHODS Retrospective analysis of a cohort receiving zidovudine, lamivudine, and either efavirenz or nevirapine with human immunodeficiency virus (HIV) RNA monitoring every 6 months. We assessed viremia (HIV RNA >1000 copies/mL after initial HIV RNA response) and resuppression (HIV RNA <400 copies/mL after viremia). Genotypic resistance testing was performed using stored plasma on a subset of patients at first detection of viremia and subsequently among patients with persistent viremia. RESULTS Between 2002 and 2006, 3727 patients initiated cART (median CD4, 147 cells/mm(3)). Of 1007 patients who developed viremia, 815 had subsequent HIV RNA assays, and 331 (41%) of these resuppressed without regimen switch. At identification of viremia, 45 (66%) of 68 patients had HIV-1 drug resistance, 42 (62%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 25 (37%) had M184V/I, and 4 (6%) had multi-nucleoside analogue drug mutations. By 12 months of persistent viremia among a subset of 14 patients with resistance testing to 12 months, 11 (78%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 8 (57%) had M184V/I, and 2 (14%) had multi-nucleoside analogue drug mutations. Resistance was associated with a reduced probability of resuppression; however, 50% of patients with NNRTI resistance resuppressed while receiving an NNRTI. CONCLUSIONS The majority of patients had NNRTI resistance mutations at detection of viremia. However, 41% resuppressed without regimen switch. Our findings support maximizing first-line use while minimizing risk of significant cross-resistance by implementing intensive adherence support and repeat HIV RNA testing 3-6 months after detecting viremia, with regimen switch only if viremia persists.

Does Tuberculosis Increase HIV Load

BACKGROUND The effect that tuberculosis (TB) has on human immunodeficiency virus (HIV) disease progression is not clearly understood. METHODS In an observational cohort study of HIV-infected adults in South Africa, baseline and final HIV load were compared between individuals who experienced an episode of TB (n=30) during follow-up and control subjects (n=56) matched by baseline CD4 cell count and follow-up time; linear regression modeling was used to control for confounding. RESULTS Mean HIV load was higher in the TB group than in the non-TB control group for both baseline (4.73 vs. 4.24 log(10) copies/mL; P=.003) and final values (5.02 vs. 4.34 log(10) copies/mL; P<.001). After adjustment for baseline HIV load and World Health Organization HIV stage, the difference in final HIV load was 0.24 log(10) copies/mL (95% confidence interval, -0.01 to 0.50 log(10) copies/mL; P=.06). CONCLUSIONS Poor prognosis for HIV-infected individuals after TB may be due to preexisting high HIV load rather than to the TB event itself. An episode of TB was associated with a small adjusted increase in HIV load at the end of the study--an increase that would not be regarded as clinically significant in an individual but could have some effect on HIV disease progression or HIV transmission at the population level. Prevention of TB is important for the reduction of HIV-related morbidity and mortality; however, antiretroviral therapy is required to have a major effect on survival in individuals with HIV disease.

Viremia, Resuppression, and Time to Resistance in Human Immunodeficiency Virus (HIV) Subtype C during First-Line Antiretroviral Therapy

BACKGROUND Episodes of viremia are common in African antiretroviral therapy (ART) programs. We sought to describe viremia, resuppression, and accumulation of resistance during first-line combination ART (cART) in South Africa. METHODS Retrospective analysis of a cohort receiving zidovudine, lamivudine, and either efavirenz or nevirapine with human immunodeficiency virus (HIV) RNA monitoring every 6 months. We assessed viremia (HIV RNA >1000 copies/mL after initial HIV RNA response) and resuppression (HIV RNA <400 copies/mL after viremia). Genotypic resistance testing was performed using stored plasma on a subset of patients at first detection of viremia and subsequently among patients with persistent viremia. RESULTS Between 2002 and 2006, 3727 patients initiated cART (median CD4, 147 cells/mm(3)). Of 1007 patients who developed viremia, 815 had subsequent HIV RNA assays, and 331 (41%) of these resuppressed without regimen switch. At identification of viremia, 45 (66%) of 68 patients had HIV-1 drug resistance, 42 (62%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 25 (37%) had M184V/I, and 4 (6%) had multi-nucleoside analogue drug mutations. By 12 months of persistent viremia among a subset of 14 patients with resistance testing to 12 months, 11 (78%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 8 (57%) had M184V/I, and 2 (14%) had multi-nucleoside analogue drug mutations. Resistance was associated with a reduced probability of resuppression; however, 50% of patients with NNRTI resistance resuppressed while receiving an NNRTI. CONCLUSIONS The majority of patients had NNRTI resistance mutations at detection of viremia. However, 41% resuppressed without regimen switch. Our findings support maximizing first-line use while minimizing risk of significant cross-resistance by implementing intensive adherence support and repeat HIV RNA testing 3-6 months after detecting viremia, with regimen switch only if viremia persists.