HAART; tuberculosis; isoniazid; prevention; antiretroviral; Africa
In Southern Africa, men access HIV counseling and testing (HCT) services less than women. Innovative strategies are needed to increase uptake of testing among men. This study assessed the effectiveness of incentivized mobile HCT in reaching unemployed men in Cape Town, South Africa.
A retrospective analysis of HCT data collected between August 2008 and August 2010 from adult men accessing clinic-based stationary and non-incentivized and incentivized mobile services. Data from these three services were analyzed using descriptive statistics and log-binomial regression models.
A total of 9416 first time testers were included in the analysis: 708 were clinic-based, 4985 were non-incentivized and 3723 incentivized mobile service testers. A higher HIV prevalence was observed among men accessing incentivized mobile testing 16.6% (617/3723) compared to those attending non-incentivized mobile 5.5% (277/4985)] and clinic-based services 10.2% (72/708)]. Among men testing at the mobile service, greater proportions of men receiving incentives were self-reported first-time testers (60.1% vs. 42.0%) and had advanced disease (14.9% vs. 7.5%) compared to men testing at non-incentivized mobile services. Furthermore, compared to the non-incentivized mobile service, the incentivized service was associated with a 3-fold greater yield of newly diagnosed HIV infections. This strong association persisted in analyses adjusted for age and first-time versus repeat testing (RR 2.33 95% CI 2.03–2.57]; p<0.001).
These findings suggest that incentivized mobile testing services may reach more previously untested men and significantly increase detection of HIV infection in men.
voluntary counseling and testing; mobile services; HIV; incentives; sub-Saharan Africa
HIV; antiretroviral; tuberculosis; smear-negative; transmission; nosocomial
To determine the short-term and long-term risks of tuberculosis (TB) associated with CD4 cell recovery during antiretroviral therapy (ART).
Observational community-based ART cohort in South Africa.
TB incidence was determined among patients (n = 1480) receiving ART for up to 4.5 years in a South African community-based service. Updated CD4 cell counts were measured 4-monthly. Person-time accrued within a range of CD4 cell count strata (CD4 cell strata) was calculated and used to derive CD4 cell-stratified TB rates. Factors associated with incident TB were identified using Poisson regression models.
Two hundred and three cases of TB were diagnosed during 2785 person-years of observation (overall incidence, 7.3 cases/100 person-years). During person-time accrued within CD4 cell strata 0–100, 101–200, 201–300, 301–400, 401–500 and more than 500 cells/µl unadjusted TB incidence rates were 16.8, 9.3, 5.5, 4.6, 4.2 and 1.5 cases/100 person-years, respectively (P < 0.001). During early ART (first 4 months), adjusted TB rates among those with CD4 cell counts 0–200 cells/µl were 1.7-fold higher than during long-term ART (P = 0.026). Updated CD4 cell counts were the only patient characteristic independently associated with long-term TB risk.
Updated CD4 cell counts were the dominant predictor of TB risk during ART in this low-resource setting. Among those with baseline CD4 cell counts less than 200 cells/µl, the excess adjusted risk of TB during early ART was consistent with ‘unmasking’ of disease missed at baseline screening. TB incidence rates at CD4 cell counts of 200–500 cells/µl remained high and adjunctive interventions are required. TB prevention would be improved by ART policies that minimized the time patients spend with CD4 cell counts below a threshold of 500 cells/µl.
Africa; antiretroviral; CD4 cell; HIV; immune reconstitution; resource-limited country; tuberculosis
Purpose of review
We review recently published literature concerning the optimum time to start antiretroviral therapy (ART) in patients with HIV-associated opportunistic infections (OIs).
In addition to data from observational studies, results from six randomised controlled clinical trials were available by July 2010. The collective findings of these trials were that patients with CD4 cell counts <200 cells/μL who start ART within the first two weeks of treatment for OIs including Pneumocystis jirovecii pneumonia, serious bacterial infections or pulmonary tuberculosis have lower mortality when compared to patients starting ART at later time-points. Moreover, patients with pulmonary tuberculosis and CD4 counts of 200-500 cells/μL who started ART during TB treatment had improved survival compared to those who deferred ART until after the end of treatment. In contrast, in two separate studies, immediate ART conferred no survival benefit in patients with TB meningitis and was associated with substantially higher mortality risk in patients with cryptococcal meningitis.
Initiation of ART during the first 2 weeks of treatment for serious opportunistic infections has been shown to be associated with improved survival with the exception of patients with tuberculous meningitis and cryptococcal meningitis. Further clinical trials are ongoing.
HIV; opportunistic infection; when to start; timing; antiretroviral
Antiretroviral therapy (ART) has been proposed as an intervention for reducing tuberculosis (TB) burdens in areas with high HIV prevalence. However, little data is available on the impact of ART on population-level TB.
Trends in adult TB case fatality and notifications were assessed prior to and during increasing ART coverage in a well-defined peri-urban community, from 1997 to 2008. Mean changes in TB rates were measured using linear autoregression models. ART coverage increased from 1% in 2003, to 5%, 13% and 21% of HIV-infected population in 2004, 2005 and 2008 respectively.
From 1997 to end of 2004 TB notification rates increased by an average of 187 cases/100,000/yr (p<0.001), reaching a peak of 2,536/100,000 in 2005. From 2005 to 2008, TB notification rates declined by approximately 183 cases/100,000/yr (p<0.001). TB rates were initially stable in HIV-uninfected individuals, but declined moderately from 2005. TB rates declined in HIV-infected adults from 6,513/100,000 in 2005 to 4,741/100,000 in 2008. The predominant decline in TB notifications occurred among HIV-infected patients receiving ART (1,156 cases/100,000/yr) and was less marked in those not receiving ART (416cases/100,000/yr). Similarly, TB case fatality was constant for HIV-uninfected individuals but declined in HIV-infected individuals from 23% in 2002 to 8% in 2008 (p=0.01).
In this community heavily affected by both HIV and TB epidemics, rapid and high ART coverage was associated with significant reductions in TB notifications and TB-associated case fatality.
tuberculosis; notification rates; HIV; antiretroviral; community
To determine the diagnostic accuracy of World Health Organization (WHO) 2010 and 2006 as well as United States Department of Health and Human Services (DHHS) 2008 definitions of immunological failure for identifying virological failure in children on antiretroviral therapy (ART).
Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/percent and HIV-RNA monitoring are performed 6-monthly. Incomplete virological suppression (IVS) was defined as failure to achieve ≥1 HIV-RNA ≤400 copies/mL between 6 and 15 months on ART and viral rebound (VR) as confirmed HIV-RNA ≥5000 copies/mL in a child on ART for ≥18 months who had achieved suppression during the first year on treatment.
Among 3115 children (median (IQR) age 48 (20-84) months at ART initiation) on treatment for ≥1 year, sensitivity of immunological criteria for IVS was 10%, 6% and 26% for WHO 2006
2010 and DHHS 2008 criteria respectively. The corresponding positive predictive values (PPV) were 31% 20% and 20%. Diagnostic accuracy for VR was determined in 2513 children with ≥18 months of follow-up and virological suppression during the first year on ART with sensitivity of 5% (WHO 2006/2010) and 27% (DHHS 2008). PPV results were 42% (WHO 2010), 43% (WHO 2006) and 20% (DHHS 2008).
Current immunological criteria are unable to correctly identify children failing ART virologically. Improved access to viral load testing is needed to reliably identify virological failure in children.
children; antiretroviral therapy; immunological criteria; sensitivity, specificity; virological failure
To assess sustainability of programmatic outcomes in a community-based antiretroviral therapy (ART) service in South Africa during 7 years scale-up.
Prospective cohort of treatment-naïve patients aged ≥15 years enrolled between 2002 and 2008. Data were analyzed by calendar period of ART initiation using time to-event analysis and logistic regression.
ART was initiated by 3162 patients (67% female, median age 34 years) who were followed-up for a median of 2.4 years (IQR,1.2-3.8). After 6 years, the cumulative probability of death and loss to follow-up (LTFU) was 37.4%. The probabilities of transfer-out to another ART service and of virological failure were 21.6% and 23.1%, respectively. Low mortality risk and excellent virological and immunological responses during the first year of ART were not associated with calendar period of ART initiation. In contrast, risk of LTFU and virological failure both increased between successive calendar periods in unadjusted and adjusted analyses. The number of patients per member of clinic staff increased markedly over time.
Successful early outcomes (low mortality and good immunological and virological responses) were sustained between sequential calendar periods during 7 years of scale-up. In contrast, the increasing cumulative probabilities of LTFU or virological failure may reflect decreasing capacity to adequately support patients long-term as clinic case-load escalated.
Antiretroviral; outcomes; mortality; loss to follow-up; virological failure; Africa
To determine the relationship between mortality risk and the CD4 cell response to antiretroviral therapy (ART).
Observational community-based ART cohort in South Africa.
CD4 cell counts were measured 4 monthly, and deaths were prospectively ascertained. Cumulative person-time accrued within a range of updated CD4 cell count strata (CD4 cell-strata) was calculated and used to derive CD4 cell-stratified mortality rates.
Patients (2423) (median baseline CD4 cell count of 105 cells/ml) were observed for up to 5 years of ART. One hundred and ninety-seven patients died during 3155 person years of observation. In multivariate analysis, mortality rate ratios associated with 0–49, 50–99, 100–199, 200–299, 300– 399, 400–499 and at least 500 cells/ml updated CD4 cell-strata were 11.6, 4.9, 2.6, 1.7, 1.5, 1.4 and 1.0, respectively. Analysis of CD4 cell count recovery permitted calculations of person-time accrued within these CD4 cell strata. Despite rapid immune recovery, high mortality in the first year of ART was related to the large proportion of person-time accrued within CD4 cell-strata less than 200 cells/ml. Moreover, patients with baseline CD4 cell counts less than 100 cells/ml had much higher cumulative mortality estimates at 1 and 4 years (11.6 and 16.7%) compared with those of patients with baseline counts of at least 100 cells/ml (5.2 and 9.5%) largely because of greater cumulative person-time at CD4 cell counts less than 200 cells/ml. Conclusion: Updated CD4 cell counts are the variable most strongly associated with mortality risk during ART. High cumulative mortality risk is associated with person-time accrued at low CD4 cell counts. National HIV programmes in resource-limited settings should be designed to minimize the time patients spend with CD4 cell counts less than 200 cells/ml both before and during ART.
Africa; antiretroviral; antiretroviral therapy; CD4; death; HIV; immune reconstitution; immune recovery; mortality
Purpose of review
We review recently published literature concerning early morbidity and mortality during antiretroviral therapy (ART) among patients in resource-limited settings. We focus on articles providing insights into this burden of disease and strategies to address it.
In sub-Saharan Africa mortality rates during the first year of ART are very high (8%-26%), with most deaths occurring in the first few months. This compares to 3%-13% in programmes in Latin America and the Caribbean and 11%-13% in South-East Asia. Risk factors generally reflect late presentation with advanced symptomatic disease. Key causes of morbidity and mortality include tuberculosis, acute sepsis, cryptococcal meningitis, malignancy, wasting syndrome/chronic diarrhoea. Current literature shows the fundamental need is for much earlier HIV diagnosis and initiation of ART. In addition, further studies provide data on the role of screening and prophylaxis against opportunistic diseases (particularly TB, bacterial sepsis and cryptococcal disease) and the management of specific opportunistic diseases and complications of ART. Effective and sustainable delivery of these interventions requires strengthening of programmes.
Strategies to address this disease burden should include earlier HIV diagnosis and ART initiation, screening and prophylaxis for opportunistic infections, optimised management of specific diseases and treatment complications, and programme strengthening.
HIV; antiretroviral; mortality; death; morbidity; resource-limited; low-income
To determine the baseline prevalence of tuberculosis (TB) in a cohort using a strategy of intensive pretreatment screening for TB and the subsequent incidence rate and temporal distribution of cases during the first year of antiretroviral therapy (ART).
Prospective observational community-based ART cohort in South Africa.
Adults enrolling for ART and who did not have a current TB diagnosis were intensively screened for TB at baseline using culture of two sputum samples, chest radiography and investigations for extrapulmonary disease as required. Patients who developed symptoms consistent with incident TB during ART were similarly investigated.
Two hundred forty-one patients had a median CD4 cell count of 125 cells/μl (interquartile range 70–186) and 200 (83%) started ART. TB was diagnosed in 87 (36%) patients, with 82% of pulmonary cases being culture-proven. Most TB cases (87%) were prevalent disease detectable at baseline, whereas just 11 (13%) were incident cases that presented during the first year of ART. The incidence rate during 0–4 months of ART was similar to the rate during months 5–12 of ART [10.9 (95% confidence interval [CI] 4.6–23.3) cases per 100 person-years versus 8.1 (95% CI 3.6–18.0) cases per 100 person-years].
Systematic culture-based screening detected a very high burden of prevalent TB present at baseline. This intensified screening strategy was associated with an approximately two-fold lower incidence rate in the first 4 months of ART than previously observed in this cohort. This suggests that many incident cases of symptomatic TB presenting during early ART can be detected as prevalent disease prior to ART initiation using sensitive diagnostic tests.
Some evidence suggests that HIV infection is associated with premature frailty -a syndrome typically viewed as being related to ageing. We determined the prevalence and predictors of frailty in a population of HIV-infected individuals in South Africa.
Case-control study of 504 adults over the age of 30 years, composed of 248 HIV-infected adults and 256 age- and gender- frequency-matched HIV-seronegative individuals.
Frailty was defined by standardized assessment comprised of ≥3 of: weight loss, low physical activity, exhaustion, weak grip strength and slow walking time. Independent predictors of frailty were evaluated using multivariable logistic regression.
The mean ages of the HIV-infected and HIV-seronegative groups were 41.1±7.9 years and 42.6±9.6 years respectively. Of the HIV-infected adults, 87.1% were receiving antiretroviral treatment (ART) (median duration, 58 months), their median CD4 count was 468 cells/μL (IQR:325-607 cells/μL) and 84.3% had undetectable plasma viral load. HIV-infected adults were more likely to be frail than HIV-seronegative individuals (19.4% vs.13.3%;p=0.07), and this association persisted after adjustment for confounding variables (adjusted odds ratio [OR] 2.14; 95% confidence interval [95%CI]: 1.16-3.92, p=0.01). Among HIV-infected individuals, older age was a strong predictor of frailty, especially among women (women: OR=2.55 per 10-year age increase; men: OR=1.29 per 10 year age increase, p-interaction=0.01). Lower current CD4 count (<500 cells/μL) was also independently associated with frailty (OR=2.84;95%CI:1.02-7.92, p=0.04).
HIV infection is associated with premature development of frailty, especially in women. Since higher CD4 counts were associated with lower risk of frailty, earlier initiation of ART may be protective.
HIV; AIDS; frailty; premature ageing; South Africa
Tenofovir (TDF) is increasingly used in second-line antiretroviral treatment (ART) in sub-Saharan Africa. We compared outcomes of second-line ART containing and not containing TDF in cohort studies from Zambia and the Republic of South Africa (RSA).
Patients aged ≥ 16 years starting protease inhibitor-based second-line ART in Zambia (1 cohort) and RSA (5 cohorts) were included. We compared mortality, immunological failure (all cohorts) and virological failure (RSA only) between patients receiving and not receiving TDF. Competing risk models and Cox models adjusted for age, sex, CD4 count, time on first-line ART and calendar year were used to analyse mortality and treatment failure, respectively. Hazard ratios (HRs) were combined in fixed-effects meta-analysis.
1,687 patients from Zambia and 1,556 patients from RSA, including 1,350 (80.0%) and 206 (13.2%) patients starting TDF, were followed over 4,471 person-years. Patients on TDF were more likely to have started second-line ART in recent years, and had slightly higher baseline CD4 counts than patients not on TDF. Overall 127 patients died, 532 were lost to follow-up and 240 patients developed immunological failure. In RSA 94 patients had virologic failure. Combined HRs comparing tenofovir with other regimens were 0.60 (95% CI 0.41–0.87) for immunologic failure and 0.63 (0.38–1.05) for mortality. The HR for virologic failure in RSA was 0.28 (0.09–0.90).
In this observational study patients on TDF-containing second-line ART were less likely to develop treatment failure than patients on other regimens. TDF seems to be an effective component of second-line ART in southern Africa.
Tenofovir; second-line antiretroviral therapy; southern Africa; treatment failure; mortality
N348I emerges frequently with failure of first-line antiretroviral therapy (ART) in subtype C human immunodeficiency virus type 1 infection and affects susceptibility to nevirapine, efavirenz, etravirine, and zidovudine. This finding has implications for cross-resistance to subsequent ART regimens in resource-limited settings.
Background. It is not known how often mutations in the connection and ribonuclease H domains of reverse transcriptase (RT) emerge with failure of first-line antiretroviral therapy (ART) in subtype C human immunodeficiency virus type 1 (HIV-1) infection and how these mutations affect susceptibility to other antiretrovirals.
Methods. We compared full-length RT sequences in plasma obtained before therapy and at virologic failure of initial ART among 63 participants with subtype C HIV-1 infection enrolled in the Comprehensive International Program of Research on AIDS in South Africa (CIPRA-SA) study. Recombinant viruses containing full-length plasma-derived RT sequences from participants with N348I at virologic failure were assayed for drug susceptibility.
Results. Y181C and M184V mutations in the RT polymerase domain were associated with failure of stavudine-lamivudine-nevirapine (d4T/3TC/NVP; P < .01), and K103N, V106M, and M184V with failure of d4T/3TC/efavirenz (EFV; P < .01). N348I in the RT connection domain emerged in 45% (P = .002) and 12% (P = .06) of participants receiving failing regimens containing NVP or EFV, respectively. Longitudinal analyses revealed that nonnucleoside RT inhibitor resistance mutations in the polymerase domain generally appeared first. N348I emerged at the same time, or after, M184V. N348I in the context of polymerase domain mutations reduced susceptibility to NVP (8.9–13-fold), EFV (4–56-fold), etravirine (ETV; 1.9–4.7-fold) and decreased hypersusceptibility to zidovudine (AZT; 1.4–2.2-fold).
Conclusions. N348I emerges frequently with virologic failure of first-line ART in subtype C HIV-1 infection and reduces susceptibility to NVP, EFV, ETV, and AZT. Additional studies are warranted to characterize the effects of N348I on virologic response to second- and third-line regimens in resource-limited settings where subtype C predominates.
In low-income settings treatment failure is often identified using CD4 cell count monitoring. Consequently, patients remain on a failing regimen, resulting in a higher risk of transmission. We investigated the benefit of routine viral load monitoring for reducing HIV transmission.
We developed a stochastic mathematical model representing the course of individual viral load, immunological response and survival in a cohort of 1,000 HIV infected patients receiving antiretroviral therapy (ART) in southern Africa. We calculated cohort viral load (sum of individual viral loads) and used a mathematical relationship between individual viral load values and transmission probability to estimate the number of new HIV infections. Our model was parameterized with data from the IeDEA Southern African collaboration. Sensitivity analyses were performed to assess the validity of the results in a universal ‘test and treat’ scenario where patients start ART earlier after HIV infection.
If CD4 cell count alone was regularly monitored, the cohort viral load was 2.6*106 copies/mL and the treated patients transmitted on average 6.3 infections each year. With routine viral load monitoring, both cohort viral load and transmissions were reduced by 31% to 1.7*106 copies/mL and 4.3 transmissions, respectively. The relative reduction of 31% between monitoring strategies remained similar for different scenarios.
While routine viral load monitoring enhances the preventive effect of ART, the provision of ART to everyone in need should remain the highest priority.
mathematical model; Southern Africa; HIV transmission; viral load monitoring; therapy failure; second-line therapy; test and treat
Background. Recent mathematical models suggested that frequent human immunodeficiency virus (HIV) testing with immediate initiation of antiretroviral therapy (ART) to individuals with a positive test result could profoundly curb transmission. The debate about ART as prevention has focused largely on parameter values. We aimed to evaluate structural assumptions regarding linkage to care and population mobility, which have received less attention.
Methods. We modified the linkage structure of published models of ART as prevention, such that individuals who decline initial testing or treatment do not link to care until late-stage HIV infection. We then added population mobility to the models. We populated the models with demographic, clinical, immigration, emigration, and linkage data from a South African township.
Results. In the refined linkage model, elimination of HIV transmission (defined as an incidence of <0.1%) did not occur by 30 years, even with optimistic assumptions about the linkage rate. Across a wide range of estimates, models were more sensitive to structural assumptions about linkage than to parameter values. Incorporating population mobility further attenuated the reduction in incidence conferred by ART as prevention.
Conclusions. Linkage to care and population mobility are critical features of ART-as-prevention models. Clinical trials should incorporate relevant data on linkage to care and migration to evaluate the impact of this strategy.
To measure rates and predictors of virologic failure and switch to second-line ART in South Africa.
Observational cohort study
We included ART-naïve adult patients initiated on public-sector ART (Jan 2000–July 2008) at five 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.
19,645 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 96 (IQR:40–159) cells/μl at ART initiation. 9.9% (4.5/100 person-years) failed ART in median 16 (IQR:12–23) months since ART initiation, with median 2.9 (IQR:1.8–5.0) months between first elevated and confirmatory viral loads. By survival analysis, using a confirmatory threshold of 400 copies/ml, 16.9% (95%CI:15.4–18.6%) failed by five years on ART, but only 7.8% (95%CI:6.6%-9.3%) using a threshold of 10,000. CD4 <25 vs. 100–199 (adjusted HR:1.57;95%CI 1.35–1.83), ART initiation viral load ≥1,000,000 vs. <10,000, (1.32;0.91–1.93) and 2+ gaps in care vs. 0 (95%CI:6.61; 4.52–9.68) were predictive of failure. Overall 10.1% (95%CI:9.0%-11.4%) switched to second-line by five years on ART. Lower CD4 at failure and higher rate of CD4 decline were predictive of switch (decline 100% to 51% vs. 25% to −25%, adjusted HR:1.96;95%CI:1.35–2.85).
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 post-failure evolution.
HIV; AIDS; antiretroviral therapy; viral load; virologic treatment failure; second line
To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment.
Analysis of 10 treatment programmes in Africa and South America that monitor both CD4 cell counts and HIV-1 viral load. Adult patients with at least two CD4 counts and viral load measurements between month 6 and 18 after starting a non-nucleoside reverse transcriptase inhibitor-based regimen were included. WHO immunological criteria include CD4 counts persistently <100 cells/μl, a fall below the baseline CD4 count, or a fall of >50% from the peak value. Virological failure was defined as two measurements ≥10 0000 copies/ml (higher threshold) or ≥500 copies/ml (lower threshold). Measures of accuracy with exact binomial 95% confidence intervals (CI) were calculated.
A total of 2009 patients were included. During 1856 person-years of follow up 63 patients met the immunological criteria and 35 patients (higher threshold) and 95 patients (lower threshold) met the virological criteria. Sensitivity [95% confidence interval (CI)] was 17.1% (6.6–33.6%) for the higher and 12.6% (6.7–21.0%) for the lower threshold. Corresponding results for specificity were 97.1% (96.3–97.8%) and 97.3% (96.5–98.0%), for positive predictive value 9.5% (3.6–19.6%) and 19.0% (10.2–30.9%) and for negative predictive value 98.5% (97.9–99.0%) and 95.7% (94.7–96.6%).
The positive predictive value of the WHO immunological criteria for virological failure of antiretroviral treatment in resource-limited settings is poor, but the negative predictive value is high. Immunological criteria are more appropriate for ruling out than for ruling in virological failure in resource-limited settings.
highly active antiretroviral therapy; treatment failure; CD4 lymphocyte count; viral load; diagnostic techniques and procedures; Africa
We studied the time interval between starting tuberculosis treatment and commencing antiretroviral treatment (ART) in HIV-infected patients (n=1433; median CD4 count 71 cells/μL, IQR,32-132) attending three South African township ART services between 2002-2008. The overall median delay was 2.66 months (IQR,1.58-4.17). In adjusted analyses, delays varied between treatment sites but were shorter for patients with lower CD4 counts and those treated in more recent calendar years. During the most recent period (2007-2008), 4.7%, 19.7% and 51.1% of patients started ART within 2, 4 and 8 weeks of TB treatment, respectively. Operational barriers must be tackled to permit further acceleration of ART initiation as recommended by 2010 WHO ART guidelines.
tuberculosis; antiretroviral; timing; delay; Africa
Cryptococcal meningitis (CM)-related mortality may be prevented by screening patients for sub-clinical cryptococcal antigenaemia (CRAG) at antiretroviral-therapy (ART) initiation and pre-emptively treating those testing positive. Prior to programmatic implementation in South Africa we performed a cost-effectiveness analysis of alternative preventive strategies for CM.
Using South African data we modelled the cost-effectiveness of four strategies for patients with CD4 cell-counts <100 cells/µl starting ART 1) no screening or prophylaxis (standard of care), 2) universal primary fluconazole prophylaxis, 3) CRAG screening with fluconazole treatment if antigen-positive, 4) CRAG screening with lumbar puncture if antigen-positive and either amphotericin-B for those with CNS disease or fluconazole for those without. Analysis was limited to the first year of ART.
The least costly strategy was CRAG screening followed by high-dose fluconazole treatment of all CRAG-positive individuals. This strategy dominated the standard of care at CRAG prevalence ≥0.6%. Although CRAG screening followed by lumbar puncture in all antigen-positive individuals was the most effective strategy clinically, the incremental benefit of LPs and amphotericin therapy for those with CNS disease was small and additional costs were large (US$158 versus US$51per person year; incremental cost effectiveness ratio(ICER) US$889,267 per life year gained). Both CRAG screening strategies are less costly and more clinically effective than current practice. Primary prophylaxis is more effective than current practice, but relatively cost-ineffective (ICER US$20,495).
CRAG screening would be a cost-effective strategy to prevent CM-related mortality among patients initiating ART in South Africa. These findings provide further justification for programmatic implementation of CRAG screening.
Increasing evidence suggests that neutrophils play a role in the host response to Mycobacterium tuberculosis. We determined whether neutrophil counts in peripheral blood are associated with tuberculosis (TB) and with mycobacterial load in sputum in HIV-infected patients.
Adults enrolling in an antiretroviral treatment (ART) clinic in a Cape Town township were screened for TB regardless of symptoms. Paired sputum samples were examined using liquid culture, fluorescence microscopy, and the Xpert MTB/RIF assay. Absolute neutrophil counts (ANC) were measured in blood samples. Of 602 HIV-infected patients screened, 523 produced one or more sputum samples and had complete results available for analysis. Among these 523 patients, the median CD4 count was 169×109/L (IQR, 96–232) and median ANC was 2.6×109/L (IQR, 1.9–3.6). Culture-positive pulmonary tuberculosis was diagnosed in 89 patients. Patients with TB had a median ANC of 3.4×109/L (IQR, 2.4–5.1) compared to 2.5×109/L (IQR, 1.8–3.4) among those who were culture negative (p<0.0001). In multivariable analyses, having pulmonary TB was associated with an adjusted risk ratio (aRR) of 2.6 (95%CI, 1.5–4.5) for having an ANC level that exceeded the median value (ANC ≥2.6×109/L; p = 0.0006) and an aRR of 6.8 (95%CI, 2.3–20.4) for having neutrophilia defined by a neutrophil count exceeding the upper limit of the normal range (ANC >7.5×109/L; p = 0.0005). Patients were then classified into four mutually exclusive groups with increasing sputum mycobacterial load as defined by the results of culture, Xpert MTB/RIF and sputum smear microscopy. Multivariable analyses demonstrated that increasing sputum mycobacterial load was positively associated with blood ANC ≥2.6×109/L and with neutrophilia.
Increased blood neutrophil counts were independently associated with pulmonary TB and sputum mycobacterial burden in this HIV-infected patient group. This observation supports the growing body of literature regarding the potential role for neutrophils in the host response to TB.
In resource-limited settings, successful HIV treatment scale-up has been tempered by reports of funding shortfalls. We aimed to determine the priorities, including ethical considerations, of decision makers for HIV antiretroviral programs. We conducted qualitative interviews with 12 decision makers, identified using purposive sampling. Respondents engaged in one-on-one, semi-structured interviews. We developed an Interview Guide to direct questions about key priorities and motivations for HIV antiretroviral program decision making. We evaluated textual data from the interviews to identify themes. Among 12 respondents, 10 (83%) lived and worked in South Africa. Respondents came from Western Cape, Gauteng, and KwaZulu-Natal provinces and worked primarily in urban settings. The respondents supported prioritizing individual patients based on treatment adherence, pregnancy status to prevent maternal-to-child HIV transmission and/or orphans, and severity of illness. However, priorities based on severity of illness varied, with first-come/first-serve, prioritization of the most severely ill, and prioritization of the least severely ill discussed. Respondents opposed prioritizing based on patient socioeconomic characteristics. Other priorities included the number receiving treatment; how treated patients are distributed in the population (e.g, urban/rural); and treatment policy (e.g., number of antiretroviral regimens). Motivations included humanitarian concerns; personal responsibility for individual patients; and clinical outcomes (e.g., patient-level morbidity/mortality, saving lives) and/or social outcomes (e.g., restoring patients as functional family members). Decision makers have a wide range of priorities for antiretroviral provision in South Africa, and the motivations underlying these priorities suggest at times conflicting ethical considerations for providing HIV treatment when resources are limited.
HIV; HIV/AIDS; antiretroviral therapy; antiretroviral priorities; ethics; South Africa; qualitative interviews
To project the clinical and economic outcomes of a genotype assay for selection of third-line antiretroviral therapy (ART) in resource-limited settings, as per the planned international A5288 trial (MULTI-OCTAVE).
We used the Cost-effectiveness of Preventing AIDS Complications (CEPAC)-International Model to compare three strategies for subjects who have failed second-line ART in South Africa: (1) Sustained second-line: no genotype assay, all subjects remain on second-line ART; (2) A5288: genotype to determine the resistance profile and assign an appropriate regimen; or (3) Population-based third-line: no genotype, all subjects switch to a potent third-line regimen. Model inputs are from published data in South Africa. Resistance profiles, ART regimens, and efficacy data were those used for trial planning.
Projected life expectancy for sustained second-line, A5288, and population-based third-line are 61.1, 103.8, and 104.2 months. Compared to sustained second-line ($12,460), per person lifetime costs increase for the A5288 ($39,250) and population-based ($44,120) strategies. The incremental cost-effectiveness ratio of A5288, compared to sustained second-line, is $7,500/year of life saved (YLS), and for population-based third-line, compared to A5288, is $154,500/YLS. In the A5288 strategy, very late presentation to care, coupled with lengthy delays to obtain the genotype, dramatically reduces 5-yr survival, making the population-based third-line strategy more attractive.
We project that, while the public health approach to third-line therapy is unaffordable, genotype assays and third-line ART in resource-limited settings will increase survival and be cost-effective compared to the population-based approach, supporting the value of an efficacy study.
Resource-limited setting; antiretroviral therapy; ART; ACTG; A5288; genotype; third-line ART; cost-effectiveness; HIV
Antiretroviral changes (single drug substitutions and regimen switches) limit treatment options and introduce challenges such as increased cost, monitoring and adherence difficulties. Patterns of drug substitutions and regimen switches from stavudine (d4T) and zidovudine (AZT) regimens have been well described but data on tenofovir (TDF) are more limited. This study describes the patterns and risk factors for drug changes of these antiretroviral drugs in adults.
This retrospective cohort study included HIV positive, antiretroviral treatment (ART) naïve adults aged ≥18 years who started ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor. Follow-up was censored at first drug change and analysis focused on NRTI changes only.
Between September 2002 and April 2011, 5095 adults initiated ART in Gugulethu. This comprised 948 subjects on TDF, 3438 on d4T and 709 subjects on AZT. Virological suppression rates at 1 year, regimen switching due to virological failure and overall losses to the programme were similar across the three groups. TDF had the lowest incidence rate of drug substitutions (2.6 per 100 P/Ys) compared to 17.9 for d4T and 8.5 per 100 P/Ys for AZT. Adverse drug reactions (ADRs) accounted for the majority of drug substitutions of d4T. Multivariate analysis showed that increasing age, female sex and d4T exposure were associated with increased hazard of drug substitution due to ADRs. Conversely, TDF exposure was associated with a substantially lower risk of substitution (adjusted hazards ratio 0.38; 95% CI 0.20–0.72).
Regimen switches and virological suppression were similar for patients exposed to TDF, d4T and AZT, suggesting all regimens were equally effective. However, TDF was better tolerated with a substantially lower rate of drug substitutions due to ADRs.