Mhairi Maskew

Gender differences in survival among adult patients starting antiretroviral therapy in South Africa: a multicentre cohort study.

Morna Cornell and colleagues investigate differences in mortality for HIV-positive men and women on antiretroviral therapy in South Africa.

Using vital registration data to update mortality among patients lost to follow-up from ART programmes: evidence from the Themba Lethu Clinic, South Africa

Objective  To estimate the rates of mortality in patients lost to follow‐up (LTFU) from a large urban public sector HIV clinic in South Africa.

Outcomes of Antiretroviral Treatment in Programmes with and without Routine Viral Load Monitoring in Southern Africa

Objectives:To compare outcomes of antiretroviral therapy (ART) in South Africa, where viral load monitoring is routine, with those in Malawi and Zambia, where monitoring is based on CD4 cell counts. Methods:We included 18 706 adult patients starting ART in South Africa and 80 937 patients in Zambia or Malawi. We examined CD4 responses in models for repeated measures and the probability of switching to second-line regimens, mortality and loss to follow-up in multistate models, measuring time from 6 months. Results:In South Africa, 9.8% [95% confidence interval (CI) 9.1–10.5] had switched at 3 years, 1.3% (95% CI 0.9–1.6) remained on failing first-line regimens, 9.2% (95% CI 8.5–9.8) were lost to follow-up and 4.3% (95% CI 3.9–4.8) had died. In Malawi and Zambia, more patients were on a failing first-line regimen [3.7% (95% CI 3.6–3.9], fewer patients had switched [2.1% (95% CI 2.0–2.3)] and more patients were lost to follow-up [15.3% (95% CI 15.0–15.6)] or had died [6.3% (95% CI 6.0–6.5)]. Median CD4 cell counts were lower in South Africa at the start of ART (93 vs. 132 cells/&mgr;l; P < 0.001) but higher after 3 years (425 vs. 383 cells/&mgr;l; P < 0.001). The hazard ratio comparing South Africa with Malawi and Zambia after adjusting for age, sex, first-line regimen and CD4 cell count was 0.58 (0.50–0.66) for death and 0.53 (0.48–0.58) for loss to follow-up. Conclusion:Over 3 years of ART mortality was lower in South Africa than in Malawi or Zambia. The more favourable outcome in South Africa might be explained by viral load monitoring leading to earlier detection of treatment failure, adherence counselling and timelier switching to second-line ART.

Patient retention from HIV diagnosis through one year on antiretroviral therapy at a primary health care clinic in Johannesburg, South Africa.

Objective:To compare patient retention at 3 stages of pre-antiretroviral (ART) care and 2 stages of post-ART care to identify when greatest attrition occurs. Design:An observational cohort study. Methods:We reviewed files of all adult nonpregnant individuals testing HIV-positive January 1–June 30, 2010, at a primary health clinic in Johannesburg, South Africa (N = 842). We classified retention in pre-ART stage 1 (HIV diagnosis to CD4 results notification in ⩽3 months), pre-ART stage 2 (initially ineligible for ART with repeat CD4 test ⩽1 year of prior CD4), pre-ART stage 3 (initiating ART ⩽3 months after first eligible CD4 result), and at 0–6 and 6–12 months post-ART. Results:Retention among all patients during pre-ART stage 1 was 69.8% [95% confidence interval (CI): 66.7% to 72.9%]. For patients initially ART ineligible (n = 221), 57.4% (95% CI: 49.5% to 65.0%) returned for a repeat CD4 during pre-ART stage 2. Among those who were ART eligible (n = 589), 73.5% (95% CI: 69.0% to 77.6%) were retained during pre-ART stage 3. Retention increased with time on ART, from 80.2% (95% CI: 75.3% to 84.5%) at 6 months to 95.3% (95% CI: 91.7% to 97.6%) between 6 and 12 months. Cumulative retention from diagnosis to 12 months on ART was 36.9% (95% CI: 33.0% to 41.1%) for those ART eligible and 43.0% (95% CI: 36.4% to 49.8%) from diagnosis to repeat CD4 testing within one year among those ART ineligible. Conclusions:Patient attrition in the first year after HIV diagnosis was greatest before ART initiation: more than 25% at each of 3 pre-ART stages. As countries expand HIV testing and ART programs, success will depend on linkage to care, especially before ART eligibility and initiation.

Rates and Predictors of Failure of First-line Antiretroviral Therapy and Switch to Second-line ART in South Africa

Objectives: To measure rates and predictors of virologic failure and switch to second-line antiretroviral therapy (ART) in South Africa. Design: Observational cohort study. Methods: We included ART-naive adult patients initiated on public sector ART (January 2000 to July 2008) at 5 sites in South Africa who completed ≥6 months of follow-up. We estimated cumulative risk of virologic failure (viral load ≥400 copies/mL with confirmation above varying thresholds) and switching to second-line ART. Results: Nineteen thousand six hundred forty-five patients (29,935 person-years) had a median of 1.3 years of study follow-up (1.8 years on ART) and a median CD4 count of 93 (IQR: 39–155) cells per microliter at ART initiation. About 9.9% (4.5 per 100 person-years) failed ART in median 16 (IQR: 12–23) months since ART initiation, with median 2.7 months (IQR: 1.6–4.7) months between first elevated and confirmatory viral loads. By survival analysis, using a confirmatory threshold of 400 copies per milliliter, 16.9% [95% confidence interval (CI): 15.4% to 18.6%] failed by 5 years on ART, but only 7.8% (95% CI: 6.6% to 9.3%) using a threshold of 10,000. CD4 <25 versus 100–199 (adjusted HR: 1.60; 95% CI: 1.37 to 1.87), ART initiation viral load ≥1,000,000 versus <10,000, (1.32; 0.91 to 1.93), and 2+ gaps in care versus 0 (95% CI: 7.25; 4.95 to 10.6) were predictive of failure. Overall, 10.1% (95% CI: 9.0% to 11.4%) switched to second-line by 5 years on ART. Lower CD4 at failure and higher rate of CD4 decline were predictive of switch (decline 100% to 51% versus 25% to –25%, adjusted HR: 1.96; 95% CI: 1.35 to 2.85). Conclusions: In resource-limited settings with viral load monitoring, virologic failure rates are highly sensitive to thresholds for confirmation. Despite clear guidelines there is considerable variability in switching failing patients, partially in response to immunologic status and postfailure evolution.

The prevalence of hepatitis B co-infection in a South African urban government HIV clinic

OBJECTIVE There are an estimated 350 million hepatitis B carriers worldwide. In South Africa the prevalence of mono-infection with hepatitis B has been estimated to range from 1% in urban areas to approximately 10% in rural areas. The exact prevalence of hepatitis B in the HIV-infected population has not been well established. Hepatitis B screening is not standard practice in government HIV clinics. Co-infection with hepatitis B and HIV can influence antiretroviral treatment and prognosis of both diseases. The purpose of this study was to evaluate the prevalence of hepatitis B/HIV coinfection. DESIGN This is believed to be the first prospective observational report on the prevalence of hepatitis B/HIV co-infection in South Africa. Patients on whom hepatitis B serological tests could not have been done previously were recruited from an HIV clinic in a regional hospital in Johannesburg. Standard hepatitis B serological tests were performed. RESULTS Five hundred and two participants were screened. The cohorts average age was 37 +/- 9 years and the average CD4 count was 128 cells/pi. Twenty-four (4.80%) were hepatitis B surface antigen positive. Nearly half (47%) of the participants showed some evidence of hepatitis B exposure. The risk of hepatitis B co-infection was not significantly different when analysed in terms of sex, race, CD4 count or age. Liver function tests were not a good predictor of hepatitis B infection. CONCLUSION The rate of hepatitis B infection, as defined by hepatitis B surface antigen positivity in HIV-infected individuals in urban South Africa was 5 times the rate in people who were not HIV-infected. A 5% rate of hepatitis B/HIV co-infection is a reason to increase the accessibility of tenofovir/emtricitabine (Truvada) for first-line treatment for this population.

Trivalent Inactivated Influenza Vaccine in African Adults Infected With Human Immunodeficient Virus: Double Blind, Randomized Clinical Trial of Efficacy, Immunogenicity, and Safety

BACKGROUND Data on the efficacy of trivalent, inactivated influenza vaccine (TIV) in HIV-infected adults, particularly in Africa, are limited. This study evaluated the safety, immunogenicity, and efficacy of TIV in HIV-infected adults. METHODS In Johannesburg, South Africa, we undertook a randomized, double-blind, placebo-controlled trial involving 506 HIV-infected adults. Subjects included 157 individuals who were antiretroviral treatment (ART) naive and 349 on stable-ART. Participants were randomly assigned to receive TIV or normal saline intramuscularly. Oropharyngeal swabs were obtained at illness visits during the influenza season and tested by shell vial culture and RT PCR assay for influenza virus. Immune response was evaluated by hemagglutinin antibody inhibition assay (HAI) in a nested cohort. The primary study outcome involved vaccine efficacy against influenza confirmed illness. This trial is registered with ClinicalTrials.gov, number NCT00757900. RESULTS The efficacy of TIV against confirmed influenza illness was 75.5% (95% CI: 9.2%-95.6%); with a risk difference of 0.18 per 100 person-weeks in TIV recipients. Among TIV recipients, seroconversion, measured by HAI titers, was evident in 52.6% for H1N1, 60.8% for H3N2, and 53.6% for influenza B virus. This compared with 2.2%, 2.2%, and 4.4% of placebo recipients (P < .0001). The frequency of local and systemic adverse events post-immunization was similar between study groups. CONCLUSIONS TIV immunization is safe and efficacious in African HIV-infected adults without underlying co-morbidities. Further evaluation of effectiveness is warranted in severely immunocompromized HIV-infected adults and those with co-morbidities such as tuberculosis.

Outcomes of stable HIV-positive patients down-referred from a doctor-managed antiretroviral therapy clinic to a nurse-managed primary health clinic for monitoring and treatment.

Objective:To compare clinical, immunologic and virologic outcomes among stable HIV-positive patients down-referred to a nurse-managed primary healthcare clinic (PHC) for treatment maintenance to those who remained at a doctor-managed treatment-initiation site. Design:We conducted a matched cohort analysis among stable HIV patients at the Themba Lethu Clinic in Johannesburg, South Africa. Eligible patients met the criteria for down-referral [undetectable viral load <10 months, antiretroviral therapy (ART) >11 months, CD4 cell count ≥200 cells/&mgr;l, stable weight and no opportunistic infections], regardless of whether they were down-referred to a PHC for treatment maintenance between February 2008 and January 2009. Patients were matched 1 : 3 (down-referred : treatment-initiation) using propensity scores. Methods:We calculated rates and hazard ratios (HRs) for the effect of down-referral on loss to follow-up (LTFU) and mortality and the relative risk of down-referral on viral rebound by 12 months of follow-up. Results:Six hundred and ninety-three down-referred patients were matched to 2079 treatment-initiation patients. Two (0.3%) down-referred and 32 (1.5%) treatment-initiation patients died, 10 (1.4%) down-referred and 87 (4.2%) treatment-initiation patients were lost, and 22 (3.3%) down-referred and 100 (5.6%) treatment-initiation patients experienced viral rebound by 12 months of follow-up. After adjustment, patients down-referred were less likely to die [hazard ratio (HR) 0.2, 95% confidence interval (CI) 0.04–0.8], become LTFU (HR 0.3, 95% CI 0.2–0.6) or experience viral rebound (relative risk 0.6, 95% CI 0.4–0.9) than treatment-initiation patients during follow-up. Conclusion:The utilization of nurse-managed PHCs for treatment maintenance of stable patients could decrease the burden on specialized doctor-managed ART clinics. Patient outcomes for down-referred patients at PHCs appear equal, if not better, than those achieved at ART clinics among stable patients.

High rates of survival, immune reconstitution, and virologic suppression on second-line antiretroviral therapy in South Africa.

To determine rates of survival, viral suppression, and immunologic change after 1 year on second-line antiretroviral therapy, we conducted a cohort study among 328 patients initiated on zidovudine, didanosine, and lopinavir/ritonavir. All patients who switched to standard second-line therapy at a large urban public-sector clinic in Johannesburg, South Africa, were included. A year after initiating second-line therapy 243/313 [78%; 95% confidence interval (CI) 73%-82%], subjects were alive and in care. Further, 203/262 (77%; 95% CI: 72%-82%) had a suppressed viral load by 1 year. Mean CD4 gain by 12 months was 133 cells/μL (95% CI: 106-160). Patients on second-line therapy had a small decreased likelihood of being alive and in care by 1 year [hazard ratio (HR) 0.84; 95% CI: 0.73-0.97] as time-matched comparisons on first-line antiretroviral therapy (ART). Patients switched before 2 viral loads >1000 (HR 1.68; 95% CI: 1.08-2.61), and those switched for reasons not related to noncompliance with first-line (HR 1.83; 95% CI: 1.14-2.93) were more likely to achieve virologic suppression by 1 year on second-line ART. As rates of treatment failure over the first year on second-line therapy were low, provision of second-line treatment to patients who fail their first-line ART should be considered a high priority in resource-poor settings.

Relationship between renal dysfunction, nephrotoxicity and death among HIV adults on tenofovir.

Objective:In April 2010, the South African government added tenofovir disoproxil fumarate to its first-line antiretroviral therapy (ART) for HIV patients. We analyzed the relationship between renal dysfunction at tenofovir initiation, nephrotoxicity and mortality. Design:Cohort analysis of HIV-infected adults who received tenofovir and had a creatinine clearance done at initiation at the Themba Lethu Clinic, Johannesburg, South Africa, between April 2004 and September 2009. Methods:We estimated the relationship between renal dysfunction, nephrotoxicity [any decline in kidney function from baseline (acute or chronic) that is secondary to a toxin (including drugs)] and mortality for patients initiated onto tenofovir-containing regimens using marginal structural models and inverse probability of treatment weights to correct estimates for lost to follow-up and confounding. Results:Of 890 patients initiated onto tenofovir, 573 (64.4%) had normal renal function (≥90 ml/min), 271 (30.4%) had mild renal dysfunction (60–89 ml/min) and 46 (5.2%) had moderate renal dysfunction (30–59 ml/min). A total of 2.4% experienced nephrotoxicity, 7.8% died and 9.7% were lost during 48 months of follow-up. Patients with mild [hazard ratio 4.8; 95% confidence interval (CI) 1.5–15.2] or moderate (hazard ratio 15.0; 95% CI 3.4–66.5) renal dysfunction were at greatest risk of nephrotoxicity, whereas those with mild (hazard ratio 1.2; 95% CI 0.7–2.3) or moderate (hazard ratio 3.2; 95% CI 1.3–7.8) renal dysfunction vs. normal renal function were at highest risk of death by 48 months. Conclusion:Much of the incident renal dysfunction in tenofovir patients is likely related to preexisting renal disorder, which may be exacerbated by tenofovir. With expanded use of tenofovir, screening for renal dysfunction prior to initiation and dose adjustment is necessary to help improve ART outcomes.