HIV status disclosure and retention in care in HIV-infected adolescents on antiretroviral therapy (ART) in West Africa

Objective

We assessed the effect of HIV status disclosure on retention in care from initiation of antiretroviral therapy (ART) among HIV-infected children aged 10 years or more in Cote d''Ivoire, Mali and Sénégal.

Methods

Multi-centre cohort study within five paediatric clinics participating in the IeDEA West Africa collaboration. HIV-infected patients were included in this study if they met the following inclusion criteria: aged 10–21 years while on ART; having initiated ART≥200 days before the closure date of the clinic database; followed ≥15 days from ART initiation in clinics with ≥10 adolescents enrolled. Routine follow-up data were merged with those collected through a standardized ad hoc questionnaire on awareness of HIV status. Probability of retention (no death or loss-to-follow-up) was estimated with Kaplan-Meier method. Cox proportional hazard model with date of ART initiation as origin and a delayed entry at date of 10th birthday was used to identify factors associated with death or loss-to-follow-up.

Results

650 adolescents were available for this analysis. Characteristics at ART initiation were: median age of 10.4 years; median CD4 count of 224 cells/mm³ (47% with severe immunosuppression), 48% CDC stage C/WHO stage 3/4. The median follow-up on ART after the age of 10 was 23.3 months; 187 adolescents (28.8%) knew their HIV status. The overall probability of retention at 36 months after ART initiation was 74.6% (95% confidence interval [CI]: 70.5–79.0) and was higher for those disclosed compared to those not: adjusted hazard ratio for the risk of being death or loss-to-follow-up = 0.23 (95% CI: 0.13–0.39).

Conclusion

About 2/3 of HIV-infected adolescents on ART were not aware of their HIV status in these ART clinics in West Africa but disclosed HIV status improved retention in care. The disclosure process should be thus systematically encouraged and organized in adolescent populations.     

High incidence of unplanned pregnancy after antiretroviral therapy initiation: findings from a prospective cohort study in South Africa

Background

Increased fertility rates in HIV-infected women receiving antiretroviral therapy (ART) have been attributed to improved immunological function; it is unknown to what extent the rise in pregnancy rates is due to unintended pregnancies.

Methods

Non-pregnant women ages 18–35 from four public-sector ART clinics in Johannesburg, South Africa, were enrolled into a prospective cohort and followed from August 2009–March 2011. Fertility intentions, contraception and pregnancy status were measured longitudinally at participants'' routine ART clinic visits.

Findings

Of the 850 women enrolled, 822 (97%) had at least one follow-up visit and contributed 745.2 person-years (PY) at-risk for incident pregnancy. Overall, 170 pregnancies were detected in 161 women (incidence rate [IR]: 21.6/100 PY [95% confidence interval (CI): 18.5–25.2]). Of the 170 pregnancies, 105 (62%) were unplanned. Unmet need for contraception was 50% higher in women initiating ART in the past year as compared to women on ART>1 year (prevalence ratio 1.5 [95% CI: 1.1–2.0]); by two years post-ART initiation, nearly one quarter of women had at least one unplanned pregnancy. Cumulative incidence of pregnancy was equally high among recent ART initiators and ART experienced participants: 23.9% [95% CI: 16.4–34.1], 15.9% [12.0–20.8], and 21.0% [16.8–26.1] for women on ART 0–1 yr, >1 yr–2 yrs, and >2 yrs respectively (log-rank, p = 0.54). Eight hormonal contraceptive failures were detected [IR: 4.4 [95% CI: 2.2–8.9], 7/8 among women using injectable methods. Overall 47% (80/170) of pregnancies were not carried to term.

Conclusions

Rates of unintended pregnancies among women on ART are high, including women recently initiating ART with lower CD4 counts and higher viral loads. A substantial burden of pregnancy loss was observed. Integration of contraceptive services and counselling into ART care is necessary to reduce maternal and child health risks related to mistimed and unwanted pregnancies. Further research into injectable contraceptive failures on ART is warranted.     

Incidence and predictors of immune reconstitution inflammatory syndrome in a rural area of Mozambique

Background

There is limited data on the epidemiology of Immune Reconstitution Inflammatory Syndrome (IRIS) in rural sub-Saharan Africa. A prospective observational cohort study was conducted to assess the incidence, clinical characteristics, outcome and predictors of IRIS in rural Mozambique.

Methods

One hundred and thirty-six consecutive antiretroviral treatment (ART)-naïve HIV-1-infected patients initiating ART at the Manhiça district hospital were prospectively followed for development of IRIS over 16 months. Survival analysis by Cox regression was performed to identify pre-ART predictors of IRIS development.

Results

Thirty-six patients developed IRIS [26.5%, incidence rate 3.1 cases/100 persons-month of ART (95% CI 2.2–4.3)]. Median time to IRIS onset was 62 days from ART initiation (IQR 35.5–93.5). Twenty-five cases (69.4%) were “unmasking”, 10 (27.8%) were “paradoxical”, and 1 (2.8%) developed a paradoxical worsening followed by the unmasking of another condition. Systemic OI (OI-IRIS) accounted for 47% (17/36) of IRIS cases, predominantly of KS (8 cases) and TB (6 cases) IRIS. Mucocutaneous IRIS manifestations (MC-IRIS) accounted for 53% (19/36) of IRIS events, mostly tinea (9 cases) and herpes simplex infection (3 cases). Multivariate analysis identified two independent predictors of IRIS development: pre-ART CD4 count <50 cells/µl (HR 2.3, 95% CI 1.19–4.44, p = 0.01) and body mass index (BMI) <18.5 (HR 2.15, 95% CI 1.07–4.3, p = 0.03). The pre-cART proportion of activated T-cells, as well as the immunologic and virologic response to ART were not associated with IRIS development. All patients continued on ART, 7 (19.4%) required hospitalization and there were 3 deaths (8.3%) attributable to IRIS.

Conclusions

IRIS is common in patients initiating ART in rural Mozambique. Pre-ART CD4 counts and BMI can easily be assessed at ART initiation in rural sub-Saharan Africa to identify patients at high risk of IRIS, for whom close supervision is warranted.     

Gender differences in immune reconstitution: a multicentric cohort analysis in sub-Saharan Africa

Background

In sub-Saharan Africa, men living with HIV often start ART at more advanced stages of disease and have higher early mortality than women. We investigated gender difference in long-term immune reconstitution.

Methods/Principal Findings

Antiretroviral-naïve adults who received ART for at least 9 months in four HIV programs in sub-Saharan Africa were included. Multivariate mixed linear models were used to examine gender differences in immune reconstitution on first line ART.A total of 21,708 patients (68% women) contributed to 61,912 person-years of follow-up. At ART start,. Median CD4 at ART were 149 [IQR 85–206] for women and 125 cells/µL [IQR 63–187] for men. After the first year on ART, immune recovery was higher in women than in men, and gender-based differences increased by 20 CD4 cells/µL per year on average (95% CI 16–23; P<0.001). Up to 6 years after ART start, patients with low initial CD4 levels experienced similar gains compared to patients with high initial levels, including those with CD4>250cells/µL (difference between patients with <50 cells/µL and those with >250 was 284 cells/µL; 95% CI 272–296; LR test for interaction with time p = 0.63). Among patients with initial CD4 count of 150–200 cells/µL, women reached 500 CD4 cells after 2.4 years on ART (95% CI 2.4–2.5) and men after 4.5 years (95% CI 4.1–4.8) of ART use.

Conclusion

Women achieved better long-term immune response to ART, reaching CD4 level associated with lower risks of AIDS related morbidity and mortality quicker than men.     

Association of age with mortality and virological and immunological response to antiretroviral therapy in rural South African adults

Objective

To assess whether treatment outcomes vary with age for adults receiving antiretroviral therapy (ART) in a large rural HIV treatment cohort.

Design

Retrospective cohort analysis using data from a public HIV Treatment & Care Programme.

Methods

Adults initiating ART 1^st August 2004 - 31^st October 2009 were stratified by age at initiation: young adults (16–24 years) mid-age adults (25–49 years) and older (≥50 years) adults. Kaplan-Meier survival analysis was used to estimate mortality rates and age and person-time stratified Cox regression to determine factors associated with mortality. Changes in CD4 cell counts were quantified using a piecewise linear model based on follow-up CD4 cell counts measured at six-monthly time points.

Results

8846 adults were included, 808 (9.1%) young adults; 7119 (80.5%) mid-age adults and 919 (10.4%) older adults, with 997 deaths over 14,778 person-years of follow-up. Adjusting for baseline characteristics, older adults had 32% excess mortality (p = 0.004) compared to those aged 25–49 years. Overall mortality rates (MR) per 100 person-years were 6.18 (95% CI 4.90–7.78); 6.55 (95% CI 6.11–7.02) and 8.69 (95% CI 7.34–10.28) for young, mid-age and older adults respectively. In the first year on ART, for older compared to both young and mid-aged adults, MR per 100 person-years were significantly higher; 0–3 months (MR: 27.1 vs 17.17 and 21.36) and 3–12 months (MR: 9.5 vs 4.02 and 6.02) respectively. CD4 count reconstitution was lower, despite better virological response in the older adults. There were no significant differences in MR after 1year of ART. Baseline markers of advanced disease were independently associated with very early mortality (0–3 months) whilst immunological and virological responses were associated with mortality after 12months.

Conclusions

Early ART initiation and improving clinical care of older adults are required to reduce high early mortality and enhance immunologic recovery, particularly in the initial phases of ART.     

Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and meta-analysis

Background

We systematically reviewed observational studies of early mortality post-antiretroviral therapy (ART) initiation in low- and middle-income countries (LMIC) in Asia, Africa, and Central and South America, as defined by the World Bank, to summarize what is known.

Methods and Findings

Studies published in English between January 1996 and December 2010 were searched in Medline and EMBASE. Three independent reviewers examined studies of mortality within one year post-ART. An article was included if the study was conducted in a LMIC, participants were initiating ART in a non-clinical trial setting and were ≥15 years. Fifty studies were included; 38 (76%) from sub-Saharan Africa (SSA), 5 (10%) from Asia, 2 (4%) from the Americas, and 5 (10%) were multi-regional. Median follow-up time and pre-ART CD4 cell count ranged from 3–55 months and 11–192 cells/mm³, respectively. Loss-to-follow-up, reported in 40 (80%) studies, ranged from 0.3%–27%. Overall, SSA had the highest pooled 12-month mortality probability of 0.17 (95% CI 0.11–0.24) versus 0.11 (95% CI 0.10–0.13) for Asia, and 0.07 (95% CI 0.007–0.20) for the Americas. Of 14 (28%) studies reporting cause-specific mortality, tuberculosis (TB) (5%–44%), wasting (5%–53%), advanced HIV (20%–37%), and chronic diarrhea (10%–25%) were most common. Independent factors associated with early mortality in 30 (60%) studies included: low baseline CD4 cell count, male sex, advanced World Health Organization clinical stage, low body mass index, anemia, age greater than 40 years, and pre-ART quantitative HIV RNA.

Conclusions

Significant heterogeneity in outcomes and in methods of reporting outcomes exist among published studies evaluating mortality in the first year after ART initiation in LMIC. Early mortality rates are highest in SSA, and opportunistic illnesses such as TB and wasting syndrome are the most common reported causes of death. Strategies addressing modifiable risk factors associated with early death are urgently needed.     

Long-term follow-up of transsexual persons undergoing sex reassignment surgery: cohort study in Sweden

Context

The treatment for transsexualism is sex reassignment, including hormonal treatment and surgery aimed at making the person''s body as congruent with the opposite sex as possible. There is a dearth of long term, follow-up studies after sex reassignment.

Objective

To estimate mortality, morbidity, and criminal rate after surgical sex reassignment of transsexual persons.

Design

A population-based matched cohort study.

Setting

Sweden, 1973-2003.

Participants

All 324 sex-reassigned persons (191 male-to-females, 133 female-to-males) in Sweden, 1973–2003. Random population controls (10∶1) were matched by birth year and birth sex or reassigned (final) sex, respectively.

Main Outcome Measures

Hazard ratios (HR) with 95% confidence intervals (CI) for mortality and psychiatric morbidity were obtained with Cox regression models, which were adjusted for immigrant status and psychiatric morbidity prior to sex reassignment (adjusted HR [aHR]).

Results

The overall mortality for sex-reassigned persons was higher during follow-up (aHR 2.8; 95% CI 1.8–4.3) than for controls of the same birth sex, particularly death from suicide (aHR 19.1; 95% CI 5.8–62.9). Sex-reassigned persons also had an increased risk for suicide attempts (aHR 4.9; 95% CI 2.9–8.5) and psychiatric inpatient care (aHR 2.8; 95% CI 2.0–3.9). Comparisons with controls matched on reassigned sex yielded similar results. Female-to-males, but not male-to-females, had a higher risk for criminal convictions than their respective birth sex controls.

Conclusions

Persons with transsexualism, after sex reassignment, have considerably higher risks for mortality, suicidal behaviour, and psychiatric morbidity than the general population. Our findings suggest that sex reassignment, although alleviating gender dysphoria, may not suffice as treatment for transsexualism, and should inspire improved psychiatric and somatic care after sex reassignment for this patient group.     

A comparison of initial antiretroviral therapy in the Swiss HIV Cohort Study and the recommendations of the International AIDS Society-USA

Background

In order to facilitate and improve the use of antiretroviral therapy (ART), international recommendations are released and updated regularly. We aimed to study if adherence to the recommendations is associated with better treatment outcomes in the Swiss HIV Cohort Study (SHCS).

Methods

Initial ART regimens prescribed to participants between 1998 and 2007 were classified according to IAS-USA recommendations. Baseline characteristics of patients who received regimens in violation with these recommendations (violation ART) were compared to other patients. Multivariable logistic and linear regression analyses were performed to identify associations between violation ART and (i) virological suppression and (ii) CD4 cell count increase, after one year.

Results

Between 1998 and 2007, 4189 SHCS participants started 241 different ART regimens. A violation ART was started in 5% of patients. Female patients (adjusted odds ratio aOR 1.83, 95%CI 1.28–2.62), those with a high education level (aOR 1.49, 95%CI 1.07–2.06) or a high CD4 count (aOR 1.53, 95%CI 1.02–2.30) were more likely to receive violation ART. The proportion of patients with an undetectable viral load (<400 copies/mL) after one year was significantly lower with violation ART than with recommended regimens (aOR 0.54, 95% CI 0.37–0.80) whereas CD4 count increase after one year of treatment was similar in both groups.

Conclusions

Although more than 240 different initial regimens were prescribed, violations of the IAS-USA recommendations were uncommon. Patients receiving these regimens were less likely to have an undetectable viral load after one year, which strengthens the validity of these recommendations.     

Antiretroviral Treatment Program Retention among HIV-Infected Children in the Democratic Republic of Congo

Background

Retaining patients with HIV infection in care is still a major challenge in sub- Saharan Africa, particularly in the Democratic Republic of Congo (DRC) where the antiretroviral treatment (ART) coverage is low. Monitoring retention is an important tool for evaluating the quality of care.

Methods and Findings

A review of medical records of HIV -infected children was performed in three health facilities in the DRC: the Amo-Congo Health center, the Monkole Clinic in Kinshasa, and the HEAL Africa Clinic in Goma. Medical records of 720 children were included. Kaplan Meier curves were constructed with the probability of retention at 6 months, 1 year, 2 years and 3 years. Retention rates were: 88.2% (95% CI: 85.1%–90.8%) at 6 months; 85% (95% CI: 81.5%–87.6%) at one year; 79.4% (95%CI: 75.5%–82.8%) at two years and 74.7% (95% CI: 70.5%–78.5%) at 3 years. The retention varied across study sites: 88.2%, 66.6% and 92.5% at 6 months; 84%, 59% and 90% at 12 months and 75.7%, 56.3% and 85.8% at 24 months respectively for Amo-Congo/Kasavubu, Monkole facility and HEAL Africa. After multivariable Cox regression four variables remained independently associated with attrition: study site, CD4 cell count <350 cells/µL, children younger than 2 years and children whose caregivers were member of an independent church.

Conclusions

Attrition remains a challenge for pediatric HIV positive patients in ART programs in DRC. In addition, the low coverage of pediatric treatment exacerbates the situation of pediatric HIV/AIDS.     

Impact of Hiv-Associated Conditions on Mortality in People Commencing Anti-Retroviral Therapy in Resource Limited Settings

Objectives

To identify associations between specific WHO stage 3 and 4 conditions diagnosed after ART initiation and all cause mortality for patients in resource-limited settings (RLS).

Design, Setting

Analysis of routine program data collected prospectively from 25 programs in eight countries between 2002 and 2010.

Subjects, Participants

36,664 study participants with median ART follow-up of 1.26 years (IQR 0.55–2.27).

Outcome Measures

Using a proportional hazards model we identified factors associated with mortality, including the occurrence of specific WHO clinical stage 3 and 4 conditions during the 6-months following ART initiation.

Results

There were 2922 deaths during follow-up (8.0%). The crude mortality rate was 5.41 deaths per 100 person-years (95% CI: 5.21–5.61). The diagnosis of any WHO stage 3 or 4 condition during the first 6 months of ART was associated with increased mortality (HR: 2.21; 95% CI: 1.97–2.47). After adjustment for age, sex, region and pre-ART CD4 count, a diagnosis of extrapulmonary cryptococcosis (aHR: 3.54; 95% CI: 2.74–4.56), HIV wasting syndrome (aHR: 2.92; 95%CI: 2.21 -3.85), non-tuberculous mycobacterial infection (aHR: 2.43; 95% CI: 1.80–3.28) and Pneumocystis pneumonia (aHR: 2.17; 95% CI 1.80–3.28) were associated with the greatest increased mortality. Cerebral toxoplasmosis, pulmonary and extra-pulmonary tuberculosis, Kaposi’s sarcoma and oral and oesophageal candidiasis were associated with increased mortality, though at lower rates.

Conclusions

A diagnosis of certain WHO stage 3 and 4 conditions is associated with an increased risk of mortality in those initiating ART in RLS. This information will assist initiatives to reduce excess mortality, including prioritization of resources for diagnostics, therapeutic interventions and research.     

Risk factors for pre-treatment mortality among HIV-infected children in rural Zambia: a cohort study

Background

Many HIV-infected children in sub-Saharan Africa enter care at a late stage of disease. As preparation of the child and family for antiretroviral therapy (ART) can take several clinic visits, some children die prior to ART initiation. This study was undertaken to determine mortality rates and clinical predictors of mortality during the period prior to ART initiation.

Methods

A prospective cohort study of HIV-infected treatment-naïve children was conducted between September 2007 and September 2010 at the HIV clinic at Macha Hospital in rural Southern Province, Zambia. HIV-infected children younger than 16 years of age who were treatment-naïve at study enrollment were eligible for analysis. Mortality rates prior to ART initiation were calculated and risk factors for mortality were evaluated.

Results

351 children were included in the study, of whom 210 (59.8%) were eligible for ART at study enrollment. Among children ineligible for ART at enrollment, 6 children died (mortality rate: 0.33; 95% CI:0.15, 0.74). Among children eligible at enrollment, 21 children died before initiation of ART and their mortality rate (2.73 per 100 person-years; 95% CI:1.78, 4.18) was significantly higher than among children ineligible for ART (incidence rate ratio: 8.20; 95% CI:3.20, 24.83). In both groups, mortality was highest in the first three months of follow-up. Factors associated with mortality included younger age, anemia and lower weight-for-age z-score at study enrollment.

Conclusions

These results underscore the need to increase efforts to identify HIV-infected children at an earlier age and stage of disease progression so they can enroll in HIV care and treatment programs prior to becoming eligible for ART and these deaths can be prevented.     

Early mortality and AIDS progression despite high initial antiretroviral therapy adherence and virologic suppression in Botswana

Background

Adverse outcomes occurring early after antiretroviral therapy (ART) initiation are common in sub-Saharan Africa, despite reports of high levels of ART adherence in this setting. We sought to determine the relationship between very early ART adherence and early adverse outcomes in HIV-infected adults in Botswana.

Methods

This prospective cohort study of 402 ART-naïve, HIV-infected adults initiating ART at a public HIV clinic in Gaborone, Botswana evaluated the relationship between suboptimal early ART adherence and HIV treatment outcomes in the initial months after ART initiation. Early adherence during the interval between initial ART dispensation and first ART refill was calculated using pill counts. In the primary analysis patients not returning to refill and those with adherence <0.95 were considered to have suboptimal early adherence. The primary outcome was death or loss to follow-up during the first 6 months of ART; a secondary composite outcome included the primary outcome plus incident opportunistic illness (OIs) and virologic failure. We also calculated the percent of early adverse outcomes theoretically attributable to suboptimal early adherence using the population attributable risk percent (PAR%).

Results

Suboptimal early adherence was independently associated with loss to follow-up and death (adjusted OR 2.3, 95% CI 1.1–4.8) and with the secondary composite outcome including incident OIs and virologic failure (adjusted OR 2.6, 95% CI 1.4–4.7). However, of those with early adverse outcomes, less than one-third had suboptimal adherence and approximately two-thirds achieved virologic suppression. The PAR% relating suboptimal early adherence and primary and secondary outcomes were 14.7% and 17.7%, respectively.

Conclusions

Suboptimal early adherence was associated with poor outcomes, but most early adverse outcomes occurred in patients with optimal early adherence. Clinical care and research efforts should focus on understanding early adverse outcomes that occur despite optimal adherence.     

Population-level reduction in adult mortality after extension of free anti-retroviral therapy provision into rural areas in northern Malawi

Background

Four studies from sub-Saharan Africa have found a substantial population-level effect of ART provision on adult mortality. It is important to see if the impact changes with time since the start of treatment scale-up, and as treatment moves to smaller clinics.

Methods and Findings

During 2002-4 a demographic surveillance site (DSS) was established in Karonga district, northern Malawi. Information on births and deaths is collected monthly, with verbal autopsies conducted for all deaths; migrations are updated annually. We analysed mortality trends by comparing three time periods: pre-ART roll-out in the district (August 2002–June 2005), ART period 1 (July 2005–September 2006) when ART was available only in a town 70 km away, and ART period 2 (October 2006–September 2008), when ART was available at a clinic within the DSS area. HIV prevalence and ART uptake were estimated from a sero-survey conducted in 2007/2008. The all-cause mortality rate among 15–59 year olds was 10.2 per 1000 person-years in the pre-ART period (288 deaths/28285 person-years). It fell by 16% in ART period 1 and by 32% in ART period 2 (95% CI 18%–43%), compared with the pre-ART period. The AIDS mortality rate fell from 6.4 to 4.6 to 2.7 per 1000 person-years in the pre-ART period, period 1 and period 2 respectively (rate ratio for period 2 = 0.43, 95% CI 0.33–0.56). There was little change in non-AIDS mortality. Treatment coverage among individuals eligible to start ART was around 70% in 2008.

Conclusions

ART can have a dramatic effect on mortality in a resource-constrained setting in Africa, at least in the early years of treatment provision. Our findings support the decentralised delivery of ART from peripheral health centres with unsophisticated facilities. Continued funding to maintain and further scale-up treatment provision will bring large benefits in terms of saving lives.     

Incidence and risk factors of serious adverse events during antituberculous treatment in Rwanda: a prospective cohort study

Background

Tuberculosis (TB) and TB-human immunodeficiency virus infection (HIV) coinfection is a major public health concern in resource-limited settings. Although TB treatment is challenging in HIV-infected patients because of treatment interactions, immunopathological reactions, and concurrent infections, few prospective studies have addressed this in sub-Saharan Africa.In this study we aimed to determine incidence, causes of, and risk factors for serious adverse events among patients on first-line antituberculous treatment, as well as its impact on antituberculous treatment outcome.

Methods and findings

Prospective observational cohort study of adults treated for TB at the Internal Medicine department of the Kigali University Hospital from May 2008 through August 2009.Of 263 patients enrolled, 253 were retained for analysis: median age 35 (Interquartile range, IQR 28–40), 55% male, 66% HIV-positive with a median CD4 count 104 cells/mm³ (IQR 44–248 cells/mm³). Forty percent had pulmonary TB, 43% extrapulmonary TB and 17% a mixed form. Sixty-four (26%) developed a serious adverse event; 58/167 (35%) HIV-infected vs. 6/86 (7%) HIV-uninfected individuals. Commonest events were concurrent infection (n = 32), drug-induced hepatitis (n = 24) and paradoxical reactions/TB-IRIS (n = 23).HIV-infection (adjusted Hazard Ratio, aHR 3.4, 95% Confidence Interval, CI 1.4–8.7) and extrapulmonary TB (aHR 2, 95%CI 1.1–3.7) were associated with an increased risk of serious adverse events. For TB/HIV co-infected patients, extrapulmonary TB (aHR 2.0, 95%CI 1.1–3.9) and CD4 count <100 cells/mm3 at TB diagnosis (aHR 1.7, 95%CI 1.0–2.9) were independent predictors. Adverse events were associated with an almost two-fold higher risk of unsuccessful treatment outcome at 6 months (HR 1.89, 95%CI 1.3–3.0).

Conclusion

Adverse events frequently complicate the course of antituberculous treatment and worsen treatment outcome, particularly in patients with extrapulmonary TB and advanced immunodeficiency. Concurrent infection accounts for most events. Our data suggest that deterioration in a patient already receiving antituberculous treatment should prompt an aggressive search for additional infections.     

Better Antiretroviral Therapy Outcomes at Primary Healthcare Facilities: An Evaluation of Three Tiers of ART Services in Four South African Provinces

Background

There are conflicting reports of antiretroviral therapy (ART) effectiveness comparisons between primary healthcare (PHC) facilities and hospitals in low-income settings. This comparison has not been evaluated on a broad scale in South Africa.

Methodology/Principal Findings

A retrospective cohort study was conducted including ART-naïve adults from 59 facilities in four provinces in South Africa, enrolled between 2004 and 2007. Kaplan-Meier estimates, competing-risks Cox regression, generalised estimating equation population-averaged models and logistic regression were used to compare death, loss to follow-up (LTFU) and virological suppression (VS) between PHC, district and regional hospitals. 29 203 adults from 47 PHC facilities, nine district hospitals and three regional hospitals were included. Patients at PHC facilities had more advanced WHO stage disease when starting ART. Retention in care was 80.1% (95% CI: 79.3%–80.8%), 71.5% (95% CI: 69.1%–73.8%) and 68.7% (95% CI: 67.0%–69.7%) at PHC, district and regional hospitals respectively, after 24 months of treatment (P<0.0001). In adjusted regression analyses, LTFU was independently increased at regional hospitals (aHR 2.19; 95% CI: 1.94−2.47) and mortality was independently elevated at district hospitals (aHR 1.60; 95% CI: 1.30−1.99) compared to PHC facilities after 12 months of ART. District and regional hospital patients had independently reduced probabilities of VS, aOR 0.76 (95% CI: 0.59−0.97) and 0.64 (95% CI: 0.56−0.75) respectively compared to PHC facilities over 24 months of treatment.

Conclusions/Significance

ART outcomes were superior at PHC facilities, despite PHC patients having more advanced clinical stage disease when starting ART, suggesting that ART can be adequately provided at this level and supporting the South African government''s call for rapid up-scaling of ART at the primary level of care. Further prospective research is required to determine the degree to which outcome differences are attributable to either facility level characteristics or patient co-morbidity at hospital level.     

Retention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review

Background

Improving the outcomes of HIV/AIDS treatment programs in resource-limited settings requires successful linkage of patients testing positive for HIV to pre–antiretroviral therapy (ART) care and retention in pre-ART care until ART initiation. We conducted a systematic review of pre-ART retention in care in Africa.

Methods and Findings

We searched PubMed, ISI Web of Knowledge, conference abstracts, and reference lists for reports on the proportion of adult patients retained between any two points between testing positive for HIV and initiating ART in sub-Saharan African HIV/AIDS care programs. Results were categorized as Stage 1 (from HIV testing to receipt of CD4 count results or clinical staging), Stage 2 (from staging to ART eligibility), or Stage 3 (from ART eligibility to ART initiation). Medians (ranges) were reported for the proportions of patients retained in each stage. We identified 28 eligible studies. The median proportion retained in Stage 1 was 59% (35%–88%); Stage 2, 46% (31%–95%); and Stage 3, 68% (14%–84%). Most studies reported on only one stage; none followed a cohort of patients through all three stages. Enrollment criteria, terminology, end points, follow-up, and outcomes varied widely and were often poorly defined, making aggregation of results difficult. Synthesis of findings from multiple studies suggests that fewer than one-third of patients testing positive for HIV and not yet eligible for ART when diagnosed are retained continuously in care, though this estimate should be regarded with caution because of review limitations.

Conclusions

Studies of retention in pre-ART care report substantial loss of patients at every step, starting with patients who do not return for their initial CD4 count results and ending with those who do not initiate ART despite eligibility. Better health information systems that allow patients to be tracked between service delivery points are needed to properly evaluate pre-ART loss to care, and researchers should attempt to standardize the terminology, definitions, and time periods reported. Please see later in the article for the Editors'' Summary     

A risk-factor guided approach to reducing lactic acidosis and hyperlactatemia in patients on antiretroviral therapy

Background

Stavudine continues to be used in antiretroviral treatment (ART) regimens in many resource-limited settings. The use of zidovudine instead of stavudine in higher-risk patients to reduce the likelihood of lactic acidosis and hyperlactatemia (LAHL) has not been examined.

Methods

Antiretroviral-naïve, HIV-infected adults initiating ART between 2004 and 2007 were divided into cohorts of those initiated on stavudine- or zidovudine-containing therapy. We evaluated stavudine or zidovudine use, age, sex, body mass index (BMI), baseline CD4 cell count, creatinine, hemoglobin, alanine aminotransferase, and albumin as predictors of time to LAHL with Cox Proportional Hazards (PH) regression models.

Results

Among 2062 patients contributing 2747 patient years (PY), the combined incidence of LAHL was 3.2/100 PY in those initiating stavudine- and 0.34/100 PY in those initiating zidovudine-containing ART (RR 9.26, 95% CI: 1.28–66.93). In multivariable Cox PH analysis, stavudine exposure (HR 14.31, 95% CI: 5.79–35.30), female sex (HR 3.41, 95% CI: 1.89–6.19), higher BMI (HR 3.21, 95% CI: 2.16–4.77), higher creatinine (1.63, 95% CI: 1.12–2.36), higher albumin (HR 1.04, 95% CI: 1.01–1.07), and lower CD4 cell count (HR 0.96, 95% CI: 0.92–1.0) at baseline were associated with higher LAHL rates. Among participants who started on stavudine, switching to zidovudine was associated with lower LAHL rates (HR 0.15, 95% CI: 0.06–0.35). Subgroup analysis limited to women with higher BMI≥25 kg/m2 initiated on stavudine also showed that switch to zidovudine was protective when controlling for other risk factors (HR 0.21, 95% CI .07–0.64).

Conclusions

Stavudine exposure, female sex, and higher BMI are strong, independent predictors for developing LAHL. Patients with risk factors for lactic acidosis have less LAHL while on zidovudine- rather than stavudine-containing ART. Switching patients from stavudine to zidovudine is protective. Countries continuing to use stavudine should avoid this drug in women and patients with higher BMI.     

Adjusting mortality for loss to follow-up: analysis of five ART programmes in sub-Saharan Africa

Background

Evaluation of antiretroviral treatment (ART) programmes in sub-Saharan Africa is difficult because many patients are lost to follow-up. Outcomes in these patients are generally unknown but studies tracing patients have shown mortality to be high. We adjusted programme-level mortality in the first year of antiretroviral treatment (ART) for excess mortality in patients lost to follow-up.

Methods and Findings

Treatment-naïve patients starting combination ART in five programmes in Côte d''Ivoire, Kenya, Malawi and South Africa were eligible. Patients whose last visit was at least nine months before the closure of the database were considered lost to follow-up. We filled missing survival times in these patients by multiple imputation, using estimates of mortality from studies that traced patients lost to follow-up. Data were analyzed using Weibull models, adjusting for age, sex, ART regimen, CD4 cell count, clinical stage and treatment programme. A total of 15,915 HIV-infected patients (median CD4 cell count 110 cells/µL, median age 35 years, 68% female) were included; 1,001 (6.3%) were known to have died and 1,285 (14.3%) were lost to follow-up in the first year of ART. Crude estimates of mortality at one year ranged from 5.7% (95% CI 4.9–6.5%) to 10.9% (9.6–12.4%) across the five programmes. Estimated mortality hazard ratios comparing patients lost to follow-up with those remaining in care ranged from 6 to 23. Adjusted estimates based on these hazard ratios ranged from 10.2% (8.9–11.6%) to 16.9% (15.0–19.1%), with relative increases in mortality ranging from 27% to 73% across programmes.

Conclusions

Naïve survival analysis ignoring excess mortality in patients lost to follow-up may greatly underestimate overall mortality, and bias ART programme evaluations. Adjusted mortality estimates can be obtained based on excess mortality rates in patients lost to follow-up.     

Can Volunteer Community Health Workers Decrease Child Morbidity and Mortality in Southwestern Uganda? An Impact Evaluation

Background

The potential for community health workers to improve child health in sub-Saharan Africa is not well understood. Healthy Child Uganda implemented a volunteer community health worker child health promotion model in rural Uganda. An impact evaluation was conducted to assess volunteer community health workers'' effect on child morbidity, mortality and to calculate volunteer retention.

Methodology/Principal Findings

Two volunteer community health workers were selected, trained and promoted child health in each of 116 villages (population ∼61,000) during 2006–2009. Evaluation included a household survey of mothers at baseline and post-intervention in intervention/control areas, retrospective reviews of community health worker birth/child death reports and post-intervention focus group discussions. Retention was calculated from administrative records. Main outcomes were prevalence of recent child illness/underweight status, community health worker reports of child deaths, focus group perception of effect, and community health worker retention. After 18–36 months, 86% of trained volunteers remained active. Post-intervention surveys in intervention households revealed absolute reductions of 10.2% [95%CI (−17.7%, −2.6%)] in diarrhea prevalence and 5.8% [95%CI (−11.5%, −0.003%)] in fever/malaria; comparative decreases in control households were not statistically significant. Underweight prevalence was reduced by 5.1% [95%CI (−10.7%, 0.4%)] in intervention households. Community health worker monthly reports revealed a relative decline of 53% in child deaths (<5 years old), during the first 18 months of intervention. Focus groups credited community health workers with decreasing child deaths, improved care-seeking practices, and new income-generating opportunities.

Conclusions/Significance

A low-cost child health promotion model using volunteer community health workers demonstrated decreased child morbidity, dramatic mortality trend declines and high volunteer retention. This sustainable model could be scaled-up to sub-Saharan African communities with limited resources and high child health needs.