Association of serum albumin with markers of nutritional status among HIV-infected and uninfected Rwandan women

Introduction

The objectives of this study are to address if and how albumin can be used as an indication of malnutrition in HIV infected and uninfected Africans.

Methods

In 2005, 710 HIV-infected and 226 HIV-uninfected women enrolled in a cohort study. Clinical/demographic parameters, CD4 count, albumin, liver transaminases; anthropometric measurements and Bioelectrical Impedance Analysis (BIA) were performed. Malnutrition outcomes were defined as body mass index (BMI), Fat-free mass index (FFMI) and Fat mass index (FMI). Separate linear predictive models including albumin were fit to these outcomes in HIV negative and HIV positive women by CD4 strata (CD4>350,200–350 and <200 cells/µl).

Results

In unadjusted models for each outcome in HIV-negative and HIV positive women with CD4>350 cells/µl, serum albumin was not significantly associated with BMI, FFMI or FMI. Albumin was significantly associated with all three outcomes (p<0.05) in HIV+ women with CD4 200–350 cells/µl, and highly significant in HIV+ women with CD4<200 cells/µl (P<0.001). In multivariable linear regression, albumin remained associated with FFMI in women with CD4 count<200 cells/µl (p<0.01) but not in HIV+ women with CD4>200.

Discussion

While serum albumin is widely used to indicate nutritional status it did not consistently predict malnutrition outcomes in HIV- women or HIV+ women with higher CD4. This result suggests that albumin may measure end stage disease as well as malnutrition and should not be used as a proxy for nutritional status without further study of its association with validated measures.     

Insulin Resistance Change and Antiretroviral Therapy Exposure in HIV-Infected and Uninfected Rwandan Women: A Longitudinal Analysis

Background

We longitudinally assessed predictors of insulin resistance (IR) change among HIV-uninfected and HIV-infected (ART-initiators and ART-non-initiators) Rwandan women.

Methodology

HIV-infected (HIV+) and uninfected (HIV-) women provided demographic and clinical measures: age, body mass index (BMI) in Kg/(height in meters)², Fat-Mass (FMI) and Fat-Free-Mass (FFMI) index, fasting serum glucose and insulin. Homeostasis Model Assessment (HOMA) was calculated to estimate IR change over time in log₁₀ transformed HOMA measured at study enrollment or prior to ART initiation in 3 groups: HIV- (n = 194), HIV+ ART-non-initiators (n=95) and HIV+ ART-initiators (n=371). ANCOVA linear regression models of change in log₁₀-HOMA were fit with all models included the first log₁₀ HOMA as a predictor.

Results

Mean±SD log₁₀-HOMA was -0.18±0.39 at the 1^st and -0.21±0.41 at the 2^nd measure, with mean change of 0.03±0.44. In the final model (all women) BMI at 1^st HOMA measure (0.014; 95% CI=0.006-0.021 per kg/m²; p<0.001) and change in BMI from 1^st to 2^nd measure (0.024; 95% CI=0.013-0.035 per kg/m²; p<0.001) predicted HOMA change. When restricted to subjects with FMI measures, FMI at 1^st HOMA measure (0.020; 95% CI=0.010-0.030 per kg/m²; p<0.001) and change in FMI from 1^st to 2^nd measure (0.032; 95% CI=0.020-0.043 per kg/m²; p<0.0001) predicted change in HOMA. While ART use did not predict change in log₁₀-HOMA, untreated HIV+ women had a significant decline in IR over time. Use or duration of AZT, d4T and EFV was not associated with HOMA change in HIV+ women.

Conclusions

Baseline BMI and change in BMI, and in particular fat mass and change in fat mass predicted insulin resistance change over ~3 years in HIV-infected and uninfected Rwandan women. Exposure to specific ART (d4T, AZT, EFV) did not predict insulin resistance change in ART-treated HIV-infected Rwandan women.     

Linkage to HIV care and antiretroviral therapy in Cape Town, South Africa

Background

Antiretroviral therapy (ART) has been scaled-up rapidly in Africa. Programme reports typically focus on loss to follow-up and mortality among patients receiving ART. However, little is known about linkage and retention in care of individuals prior to starting ART.

Methodology

Data on adult residents from a periurban community in Cape Town were collected at a primary care clinic and hospital. HIV testing registers, CD4 count results provided by the National Health Laboratory System and ART registers were linked. A random sample (n = 885) was drawn from adults testing HIV positive through antenatal care, sexual transmitted disease and voluntary testing and counseling services between January 2004 and March 2009. All adults (n = 103) testing HIV positive through TB services during the same time period were also included in the study. Linkage to HIV care was defined as attending for a CD4 count measurement within 6 months of HIV diagnosis. Linkage to ART care was defined as initiating ART within 6 months of HIV diagnosis in individuals with a CD4 count ≤200 cells/µl taken within 6 months of HIV diagnosis.

Findings

Only 62.6% of individuals attended for a CD4 count measurement within 6 months of testing HIV positive. Individuals testing through sexually transmitted infection services had the best (84.1%) and individuals testing on their own initiative (53.5%) the worst linkage to HIV care. One third of individuals with timely CD4 counts were eligible for ART and 66.7% of those were successfully linked to ART care. Linkage to ART care was highest among antenatal care clients. Among individuals not yet eligible for ART only 46.3% had a repeat CD4 count. Linkage to HIV care improved in patients tested in more recent calendar period.

Conclusion

Linkage to HIV and ART care was low in this poor peri-urban community despite free services available within close proximity. More efforts are needed to link VCT scale-up to subsequent care.     

Adherence to highly active antiretroviral treatment in HIV-infected Rwandan women

Background

Scale-up of highly active antiretroviral treatment therapy (HAART) programs in Rwanda has been highly successful but data on adherence is limited. We examined HAART adherence in a large cohort of HIV+ Rwandan women.

Methods

The Rwanda Women''s Interassociation Study Assessment (RWISA) was a prospective cohort study that assessed effectiveness and toxicity of ART. We analyzed patient data 12±3 months after HAART initiation to determine adherence rates in HIV+ women who had initiated HAART.

Results

Of the 710 HIV+ women at baseline, 490 (87.2%) initiated HAART. Of these, 6 (1.2%) died within 12 months, 15 others (3.0%) discontinued the study and 80 others (19.0%) remained in RWISA but did not have a post-HAART initiation visit that fell within the 12±3 month time points leaving 389 subjects for analysis. Of these 389, 15 women stopped their medications without being advised to do so by their doctors. Of the remaining 374 persons who reported current HAART use 354 completed the adherence assessment. All women, 354/354, reported 100% adherence to HAART at the post-HAART visit. The high self-reported level of adherence is supported by changes in laboratory measures that are influenced by HAART. The median (interquartile range) CD4 cell count measured within 6 months prior to HAART initiation was 185 (128, 253) compared to 264 (182, 380) cells/mm³ at the post-HAART visit. Similarly, the median (interquartile range) MCV within 6 months prior to HAART initiation was 88 (83, 93) fL compared to 104 (98, 110) fL at the 12±3 month visit.

Conclusion

Self-reported adherence to antiretroviral treatment 12±3 months after initiating therapy was 100% in this cohort of HIV-infected Rwandan women. Future studies should explore country-specific factors that may be contributing to high levels of adherence to HAART in this population.     

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.     

Gender difference in 2-year mortality and immunological response to ART in an HIV-infected Chinese population, 2006-2008

Background

Since it was initiated in 2002, the China Free Antiretroviral Treatment (ART) Program has been progressing from an emergency response to a standardized treatment and care system. As of December 31, 2009, a total of 81,880 patients in 31 provinces, autonomous regions, and special municipalities received free ART. Gender differences, however, in mortality and immunological response to ART in this cohort have never been described.

Objective

To understand whether women and men who enrolled in the China National Free ART Program responded equally well to the treatment.

Methods

A retrospective analysis of the national free ART databases from June 2006–December 2008 was performed. HIV-infected subjects who were 18 years or older, ART naïve at baseline, and on a 3TC regimen enrolled in the program from June 1 to December 31, 2006, were included in this study, then followed up to 2 years.

Results

Among 3457 enrolled subjects who met the inclusion criteria, 59.2% were male and 40.8% female. The majority of the subjects were 19–44 years old (77%) and married (72%). Over the full 24 months of follow-up, the mortality rate was 19.0% in males and 11.4% in females (p = 0.0014). Males on therapy for 3–24 months were more likely to die than females (HR = 1.46, 95% CI: 1.04–2.06, p = 0.0307) after adjusting for baseline characteristics. Compared to men, women had higher CD4+ counts over time after initiating ART (p<0.0001).

Conclusions

Our study showed that women had an overall lower mortality and higher CD4+ counts than men in response to ART treatment, which may be attributed to adherence, biological factors, social, cultural and economic reasons. Further study is needed to explore these factors that might contribute to the gender differences in mortality and immunological response to ART.     

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.     

Factors influencing retention in care after starting antiretroviral therapy in a rural South African programme

Introduction

The prognosis of patients with HIV in Africa has improved with the widespread use of antiretroviral therapy (ART) but these successes are threatened by low rates of long-term retention in care. There are limited data on predictors of retention in care, particularly from rural sites.

Methods

Prospective cohort analysis of outcome measures in adults from a rural HIV care programme in Madwaleni, Eastern Cape, South Africa. The ART programme operates from Madwaleni hospital and seven primary care feeder clinics with full integration between inpatient and outpatient services. Outreach workers conducted home visits for defaulters.

Results

1803 adults initiated ART from June 2005 to May 2009. At the end of the study period 82.4% were in active care or had transferred elsewhere, 11.1% had died and 6.5% were lost to follow-up (LTFU). Independent predictors associated with an increased risk of LTFU were CD4 nadir >200, initiating ART as an inpatient or while pregnant, and younger age, while being in care for >6 months before initiating ART was associated with a reduced risk. Independent factors associated with an increased risk of mortality were baseline CD4 count <50 and initiating ART as an inpatient, while being in care for >6 months before initiating ART and initiating ART while pregnant were associated with a reduced risk.

Conclusions

Serving a socioeconomically deprived rural population is not a barrier to successful ART delivery. Patients initiating ART while pregnant and inpatients may require additional counselling and support to reduce LTFU. Providing HIV care for patients not yet eligible for ART may be protective against being LTFU and dying after ART initiation.     

Maternal CD4+ Cell Count Decline after Interruption of Antiretroviral Prophylaxis for the Prevention of Mother-to-Child Transmission of HIV

Background

We evaluated maternal CD4+ cell count (CD4+) decline after PMTCT prophylaxis in a multi-country HIV care program.

Methods

Analysis was restricted to antiretroviral therapy (ART)-naive, HIV-infected pregnant women with CD4+ ≥250 cells/mm³ at enrollment. Single-dose nevirapine (sd-NVP) or short-course antiretroviral prophylaxis (sc-ARVp) with zidovudine (AZT) or AZT + lamivudine (3TC) was initiated in 11 programs while 2 programs offered triple-drug antiretroviral prophylaxis (tARVp) (AZT+3TC+ NVP or nelfinavir). All regimens were stopped at delivery. CD4+ decline was defined as proportion of women who declined to CD4+ <350 cells/mm³ or <200 cells/mm³ at 24 months. Weibull regression was used for multivariable analysis.

Findings

A total of 1,393 women with enrollment CD4+ ≥250 cells/mm³ initiated tARVp (172; 12%) or sc-ARVp (532; 38%) during pregnancy or received intrapartum sd-NVP (689; 50%). At enrollment, maternal median age was 27 years (interquartile range (IQR) 23–30), median CD4+ was 469 cells/mm³ (IQR: 363–613). At 24 months post-delivery, the cumulative probability of CD4+ decline to <200 cells/mm³ was 12% (95% CI: 10–14). Among a subgroup of 903 women with CD4+ ≥400 cells at enrollment, the 24 month cumulative probability of decline to CD4+ <350 cells/mm³ was 28%; (95% CI: 25–32). Lower antepartum CD4+ was associated with higher probability of CD4+ decline to <350 cells/mm³: 46% (CD4+400–499 cells/mm³) vs. 19% (CD4+ ≥500 cells/mm³). After adjusting for age, enrollment CD4+ and WHO stage, women who received tARVp or sd-NVP were twice as likely to experience CD4+ decline to <350 cells/mm³ within 24 months than women receiving sc-ARVp (adjusted hazard ratio: 2.2; 95% CI: 1.5–3.2, p<0.0001).

Conclusion

Decline in CD4+ cell count to ART eligibility thresholds by 24 months postpartum was common among women receiving PMTCT prophylaxis during pregnancy and/or delivery.     

Cost-effectiveness of primary prophylaxis of AIDS associated cryptococcosis in Cambodia

Background

Cryptococcal infection is a frequent cause of mortality in Cambodian HIV-infected patients with CD4+ count ≤100 cells/µl. This study assessed the cost-effectiveness of three strategies for cryptococcosis prevention in HIV-infected patients.

Methods

A Markov decision tree was used to compare the following strategies at the time of HIV diagnosis: no intervention, one time systematic serum cryptococcal antigen (CRAG) screening and treatment of positive patients, and systematic primary prophylaxis with fluconazole. The trajectory of a hypothetical cohort of HIV-infected patients with CD4+ count ≤100 cells/µl initiating care was simulated over a 1-year period (cotrimoxazole initiation at enrollment; antiretroviral therapy within 3 months). Natural history and cost data (US$ 2009) were from Cambodia. Efficacy data were from international literature.

Results

In a population in which 81% of patients had a CD4+ count ≤50 cells/ µl and 19% a CD4+ count between 51–100 cells/µl, the proportion alive 1 year after enrolment was 61% (cost $ 472) with no intervention, 70% (cost $ 483) with screening, and 72% (cost $ 492) with prophylaxis. After one year of follow-up, the cost-effectiveness of screening vs. no intervention was US$ 180/life year gained (LYG). The cost-effectiveness of prophylaxis vs. screening was $ 511/LYG. The cost-effectiveness of prophylaxis vs. screening was estimated at $1538/LYG if the proportion of patients with CD4+ count ≤50 cells/µl decreased by 75%.

Conclusion

In a high endemic area of cryptococcosis and HIV infection, serum CRAG screening and prophylaxis are two cost effective strategies to prevent AIDS associated cryptococcosis in patients with CD4+ count ≤100 cells/µl, at a short-term horizon, screening being more cost-effective but less effective than prophylaxis. Systematic primary prophylaxis may be preferred in patients with CD4+ below 50 cells/µl while systematic serum CRAG screening for early targeted treatment may be preferred in patients with CD4+ between 51–100 cells/µl.     

Risk factors for cervical precancer and cancer in HIV-infected, HPV-positive Rwandan women

Background

Although cervical cancer is an AIDS-defining condition, infection with human immunodeficiency virus (HIV) may only modestly increase the risk of cervical cancer. There is a paucity of information regarding factors that influence the natural history of human papillomavirus (HPV) in HIV-infected women. We examined factors associated with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in Rwandan women infected with both HIV and HPV (HIV+/HPV+).

Methods

In 2005, 710 HIV+ Rwandan women ≥25 years enrolled in an observational cohort study; 476 (67%) tested HPV+. Each woman provided sociodemographic data, CD4 count, a cervical cytology specimen and cervicovaginal lavage (CVL), which was tested for >40 HPV genotypes by MY09/MY11 PCR assay. Logistic regression models calculated odds ratios (OR) and 95% confidence intervals (CI) of associations of potential risk factors for CIN3+ among HIV+/HPV+ women.

Results

Of the 476 HIV+/HPV+ women 42 (8.8%) were diagnosed with CIN3+. Factors associated with CIN3+ included ≥7 (vs. 0-2) pregnancies, malarial infection in the previous six months (vs. never), and ≥7 (vs. 0-2) lifetime sexual partners. Compared to women infected by non-HPV16 carcinogenic HPV genotypes, HPV16 infection was positively associated and non-carcinogenic HPV infection was inversely associated with CIN3+. CD4 count was significantly associated with CIN3+ only in analyses of women with non-HPV16 carcinogenic HPV (OR = 0.62 per 100 cells/mm³, CI = 0.40-0.97).

Conclusions

In this HIV+/HPV+ population, lower CD4 was significantly associated with CIN3+ only in women infected with carcinogenic non-HPV16. We found a trend for higher risk of CIN3+ in HIV+ women reporting recent malarial infection; this association should be investigated in a larger group of HIV+/HPV+ women.     

Quality of life and related factors among HIV-positive spouses from serodiscordant couples under antiretroviral therapy in Henan Province, China

Objective

To describe the quality of life and related factors in HIV-positive spouses undergoing ART from discordant couples.

Methods

A cross-sectional study was conducted among 1,009 HIV-positive spouses from serodiscordant couples in Zhumadian, Henan Province, between October 1, 2008 and March 31, 2009. HIV-positive spouses were interviewed by local health professionals. Quality of life was evaluated by WHOQOL (Chinese Version). A multiple linear regression model was used to analyze the related factors.

Results

The majority of subjects were female (56.39%), had received a high school education (44%), were of Han ethnicity (98.41%), and were farmers (90.09%); the median time period of receiving ART was 3.92 years. The physical, psychological, social, and environmental QOL scores of the subjects were 12.91±1.95, 12.35±1.80, 13.96±2.43, and 12.45±1.91 respectively. The multiple linear regression model identified the physical domain related factors to be CD4 count, educational level, and occupation; psychological domain related factors include age, educational level, and reported STD symptom; social domain related factors included education level; and environmental domain related factors included education level, reported STD symptoms, and occupation.

Conclusion

Being younger, a farmer, having a lower level of education, a reported STD symptom, or lower CD4 count, could decrease one''s quality of life, suggesting that the use of blanket ART programs alone may not necessarily improve quality of life. Subjects received lower scores in the psychological domain, suggesting that psychological intervention may also need to be strengthened.     

Prolactin secretion in healthy adults is determined by gender, age and body mass index

Background

Prolactin (PRL) secretion is quantifiable as mean, peak and nadir PRL concentrations, degree of irregularity (ApEn, approximate entropy) and spikiness (brief staccato-like fluctuations).

Hypothesis

Distinct PRL dynamics reflect relatively distinct (combinations of) subject variables, such as gender, age, and BMI.

Location

Clinical Research Unit.

Subjects

Seventy-four healthy adults aged 22–77 yr (41 women and 33 men), with BMI 18.3–39.4 kg/m².

Measures

Immunofluorometric PRL assay of 10-min samples collected for 24 hours.

Results

Mean 24-h PRL concentration correlated jointly with gender (P<0.0001) and BMI (P = 0.01), but not with age (overall R² = 0.308, P<0.0001). Nadir PRL concentration correlated with gender only (P = 0.017) and peak PRL with gender (P<0.001) and negatively with age (P<0.003), overall R² = 0.325, P<0.0001. Forward-selection multivariate regression of PRL deconvolution results demonstrated that basal (nonpulsatile) PRL secretion tended to be associated with BMI (R² = 0.058, P = 0.03), pulsatile secretion with gender (R² = 0.152, P = 0.003), and total secretion with gender and BMI (R² = 0.204, P<0.0001). Pulse mass was associated with gender (P = 0.001) and with a negative tendency to age (P = 0.038). In male subjects older than 50 yr (but not in women) approximate entropy was increased (0.942±0.301 vs. 1.258±0.267, P = 0.007) compared with younger men, as well as spikiness (0.363±0.122 vs. 0463±2.12, P = 0.031). Cosinor analysis disclosed higher mesor and amplitude in females than in men, but the acrophase was gender-independent. The acrophase was determined by age and BMI (R² = 0.186, P = 0.001).

Conclusion

In healthy adults, selective combinations of gender, age, and BMI specify distinct PRL dynamics, thus requiring balanced representation of these variables in comparative PRL studies.     

Herpes simplex virus type 2, genital ulcers and HIV-1 disease progression in postpartum women

Background

Co-infection with herpes simplex virus type 2 (HSV-2) has been associated with increased HIV-1 RNA levels and immune activation, two predictors of HIV-1 progression. The impact of HSV-2 on clinical outcomes among HIV-1 infected pregnant women is unclear.

Methods

HIV-1 infected pregnant women in Nairobi were enrolled antenatally and HSV-2 serology was obtained. HIV-1 RNA and CD4 count were serially measured for 12–24 months postpartum. Survival analysis using endpoints of death, opportunistic infection (OI), and CD4<200 cells µL, and linear mixed models estimating rate of change of HIV-1 RNA and CD4, were used to determine associations between HSV-2 serostatus and HIV-1 progression.

Results

Among 296 women, 254 (86%) were HSV-2-seropositive. Only 30 (10%) women had prior or current genital ulcer disease (GUD); median baseline CD4 count was 422 cells µL. Adjusting for baseline CD4, women with GUD were significantly more likely to have incident OIs (adjusted hazard ratio (aHR) 2.79, 95% CI: 1.33–5.85), and there was a trend for association between HSV-2-seropositivity and incident OIs (aHR 3.83, 95% CI: 0.93–15.83). Rate of change in CD4 count and HIV-1 RNA did not differ by HSV-2 status or GUD, despite a trend toward higher baseline HIV-1 RNA in HSV-2-seropositive women (4.73 log10 copies/ml vs. 4.47 log10 copies/ml, P = 0.07).

Conclusions

HSV-2 was highly prevalent and pregnant HIV-1 infected women with GUD were significantly more likely to have incident OIs than women without GUD, suggesting that clinically evident HSV-2 is a more important predictor of HIV-1 disease progression than asymptomatic HSV-2.     

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.     

Gender Differences in Survival among Adult Patients Starting Antiretroviral Therapy in South Africa: A Multicentre Cohort Study

Background

Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.

Methods and Findings

Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population.Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22–1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12–1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86–1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located.

Conclusions

HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic. Please see later in the article for the Editors'' Summary.     

Drug-Resistant Tuberculosis among HIV-Infected Patients Starting Antiretroviral Therapy in Durban, South Africa

Objective

To estimate the prevalence of drug-resistant tuberculosis (TB) and describe the resistance patterns in patients commencing antiretroviral therapy (ART) in an HIV clinic in Durban, South Africa.

Design

Cross-sectional cohort study.

Methods

Consecutive HIV-infected adults (≥18y/o) initiating HIV care were enrolled from May 2007–May 2008, regardless of signs or symptoms of active TB. Prior TB history and current TB treatment status were self-reported. Subjects expectorated sputum for culture (MGIT liquid and 7H11 solid medium). Positive cultures were tested for susceptibility to first- and second-line anti-tuberculous drugs. The prevalence of drug-resistant TB, stratified by prior TB history and current TB treatment status, was assessed.

Results

1,035 subjects had complete culture results. Median CD4 count was 92/µl (IQR 42–150/µl). 267 subjects (26%) reported a prior history of TB and 210 (20%) were receiving TB treatment at enrollment; 191 (18%) subjects had positive sputum cultures, among whom the estimated prevalence of resistance to any antituberculous drug was 7.4% (95% CI 4.0–12.4). Among those with prior TB, the prevalence of resistance was 15.4% (95% CI 5.9–30.5) compared to 5.2% (95% CI 2.1–8.9) among those with no prior TB. 5.1% (95% CI 2.4–9.5) had rifampin or rifampin plus INH resistance.

Conclusions

The prevalence of TB resistance to at least one drug was 7.4% among adults with positive TB cultures initiating ART in Durban, South Africa, with 5.1% having rifampin or rifampin plus INH resistance. Improved tools for diagnosing TB and drug resistance are urgently needed in areas of high HIV/TB prevalence.     

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.     

Tuberculosis incidence rates during 8 years of follow-up of an antiretroviral treatment cohort in South Africa: comparison with rates in the community

Background

Although antiretroviral therapy (ART) is known to be associated with time-dependent reductions in tuberculosis (TB) incidence, the long-term impact of ART on incidence remains imprecisely defined due to limited duration of follow-up and incomplete CD4 cell count recovery in existing studies. We determined TB incidence in a South African ART cohort with up to 8 years of follow-up and stratified rates according to CD4 cell count recovery. We compared these rates with those of HIV-uninfected individuals living in the same community.

Methodology/Principal Findings

Prospectively collected clinical data on patients receiving ART in a community-based cohort in Cape Town were analysed. 1544 patients with a median follow-up of 5.0 years (IQR 2.4–5.8) were included in the analysis. 484 episodes of incident TB (73.6% culture-confirmed) were diagnosed in 424 patients during 6506 person-years (PYs) of follow-up. The TB incidence rate during the first year of ART was 12.4 (95% CI 10.8–14.4) cases/100PYs and decreased to 4.92 (95% CI 3.64–8.62) cases/100PYs between 5 and 8 years of ART. During person-time accrued within CD4 cell strata 0–100, 101–200, 201–300, 301–400, 401–500, 501–700 and ≥700 cells/µL, TB incidence rates (95% CI) were 25.5 (21.6–30.3), 11.2 (9.4–13.5), 7.9 (6.4–9.7), 5.0 (3.9–6.6), 5.1 (3.8–6.8), 4.1 (3.1–5.4) and 2.7 (1.7–4.5) cases/100PYs, respectively. Overall, 75% (95% CI 70.9–78.8) of TB episodes were recurrent cases. Updated CD4 cell count and viral load measurements were independently associated with long-term TB risk. TB rates during person-time accrued in the highest CD4 cell count stratum (>700 cells/µL) were 4.4-fold higher that the rate in HIV uninfected individuals living in the same community (2.7 versus 0.62 cases/100PYs; 95%CI 0.58–0.65).

Conclusions/Significance

TB rates during long-term ART remained substantially greater than rates in the local HIV uninfected populations regardless of duration of ART or attainment of CD4 cell counts exceeding 700 cells/µL.