Eduardo Sprinz

Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries

BACKGROUND Highly active antiretroviral therapy (HAART) is being scaled up in developing countries. We compared baseline characteristics and outcomes during the first year of HAART between HIV-1-infected patients in low-income and high-income settings. METHODS 18 HAART programmes in Africa, Asia, and South America (low-income settings) and 12 HIV cohort studies from Europe and North America (high-income settings) provided data for 4810 and 22,217, respectively, treatment-naïve adult patients starting HAART. All patients from high-income settings and 2725 (57%) patients from low-income settings were actively followed-up and included in survival analyses. FINDINGS Compared with high-income countries, patients starting HAART in low-income settings had lower CD4 cell counts (median 108 cells per muL vs 234 cells per muL), were more likely to be female (51%vs 25%), and more likely to start treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI) (70%vs 23%). At 6 months, the median number of CD4 cells gained (106 cells per muL vs 103 cells per muL) and the percentage of patients reaching HIV-1 RNA levels lower than 500 copies/mL (76%vs 77%) were similar. Mortality was higher in low-income settings (124 deaths during 2236 person-years of follow-up) than in high-income settings (414 deaths during 20,532 person-years). The adjusted hazard ratio (HR) of mortality comparing low-income with high-income settings fell from 4.3 (95% CI 1.6-11.8) during the first month to 1.5 (0.7-3.0) during months 7-12. The provision of treatment free of charge in low-income settings was associated with lower mortality (adjusted HR 0.23; 95% CI 0.08-0.61). INTERPRETATION Patients starting HAART in resource-poor settings have increased mortality rates in the first months on therapy, compared with those in developed countries. Timely diagnosis and assessment of treatment eligibility, coupled with free provision of HAART, might reduce this excess mortality.

Early loss of HIV-infected patients on potent antiretroviral therapy programmes in lower-income countries

OBJECTIVE To analyse the early loss of patients to antiretroviral therapy (ART) programmes in resource-limited settings. METHODS Using data on 5491 adult patients starting ART (median age 35 years, 46% female) in 15 treatment programmes in Africa, Asia and South America with (3) 12 months of follow-up, we investigated risk factors for no follow-up after treatment initiation, and loss to follow-up or death in the first 6 months. FINDINGS Overall, 211 patients (3.8%) had no follow-up, 880 (16.0%) were lost to follow-up and 141 (2.6%) were known to have died in the first 6 months. The probability of no follow-up was higher in 2003-2004 than in 2000 or earlier (odds ratio, OR: 5.06; 95% confidence interval, CI: 1.28-20.0), as was loss to follow-up (hazard ratio, HR: 7.62; 95% CI: 4.55-12.8) but not recorded death (HR: 1.02; 95% CI: 0.44-2.36). Compared with a baseline CD4-cell count (3) 50 cells/microl, a count < 25 cells/microl was associated with a higher probability of no follow-up (OR: 2.49; 95% CI: 1.43-4.33), loss to follow-up (HR: 1.48; 95% CI: 1.23-1.77) and death (HR: 3.34; 95% CI: 2.10-5.30). Compared to free treatment, fee-for-service programmes were associated with a higher probability of no follow-up (OR: 3.71; 95% CI: 0.97-16.05) and higher mortality (HR: 4.64; 95% CI: 1.11-19.41). CONCLUSION Early patient losses were increasingly common when programmes were scaled up and were associated with a fee for service and advanced immunodeficiency at baseline. Measures to maximize ART programme retention are required in resource-poor countries.

Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America

Objectives  To describe temporal trends in baseline clinical characteristics, initial treatment regimens and monitoring of patients starting antiretroviral therapy (ART) in resource‐limited settings.

Gender and the use of antiretroviral treatment in resource-constrained settings: findings from a multicenter collaboration.

AIMS To compare the gender distribution of HIV-infected adults receiving highly active antiretroviral treatment (HAART) in resource-constrained settings with estimates of the gender distribution of HIV infection; to describe the clinical characteristics of women and men receiving HAART. METHODS The Antiretroviral Therapy in Lower-Income Countries, ART-LINC Collaboration is a network of clinics providing HAART in Africa, Latin America, and Asia. We compared UNAIDS data on the gender distribution of HIV infection with the proportions of women and men receiving HAART in the ART-LINC Collaboration. RESULTS Twenty-nine centers in 13 countries participated. Among 33,164 individuals, 19,989 (60.3%) were women. Proportions of women receiving HAART in ART-LINC centers were similar to, or higher than, UNAIDS estimates of the proportions of HIV-infected women in all but two centers. There were fewer women receiving HAART than expected from UNAIDS data in one center in Uganda and one center in India. Taking into account heterogeneity across cohorts, women were younger than men, less likely to have advanced HIV infection, and more likely to be anemic at HAART initiation. CONCLUSIONS Women in resource-constrained settings are not necessarily disadvantaged in their access to HAART. More attention needs to be paid to ensuring that HIV-infected men are seeking care and starting HAART.

Long-term immunologic response to antiretroviral therapy in low-income countries: a collaborative analysis of prospective studies

Background: Few data are available on the long-term immunologic response to antiretroviral therapy (ART) in resource-limited settings, where ART is being rapidly scaled up using a public health approach, with a limited repertoire of drugs. Objectives: To describe immunologic response to ART among ART patients in a network of cohorts from sub-Saharan Africa, Latin America, and Asia. Study population/methods: Treatment-naive patients aged 15 and older from 27 treatment programs were eligible. Multilevel, linear mixed models were used to assess associations between predictor variables and CD4 cell count trajectories following ART initiation. Results: Of 29 175 patients initiating ART, 8933 (31%) were excluded due to insufficient follow-up time and early lost to follow-up or death. The remaining 19 967 patients contributed 39 200 person-years on ART and 71 067 CD4 cell count measurements. The median baseline CD4 cell count was 114 cells/μl, with 35% having less than 100 cells/μl. Substantial intersite variation in baseline CD4 cell count was observed (range 61–181 cells/μl). Women had higher median baseline CD4 cell counts than men (121 vs. 104 cells/μl). The median CD4 cell count increased from 114 cells/μl at ART initiation to 230 [interquartile range (IQR) 144–338] at 6 months, 263 (IQR 175–376) at 1 year, 336 (IQR 224–472) at 2 years, 372 (IQR 242–537) at 3 years, 377 (IQR 221–561) at 4 years, and 395 (IQR 240–592) at 5 years. In multivariable models, baseline CD4 cell count was the most important determinant of subsequent CD4 cell count trajectories. Conclusion: These data demonstrate robust and sustained CD4 response to ART among patients remaining on therapy. Public health and programmatic interventions leading to earlier HIV diagnosis and initiation of ART could substantially improve patient outcomes in resource-limited settings.

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

Background:In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia. Design and methods:Multicohort study of 17 ART programmes. All sites monitored CD4 cell count and had access to second-line ART and 10 sites monitored viral load. We compared times to switching, CD4 cell counts at switching and obtained adjusted hazard ratios for switching (aHRs) with 95% confidence intervals (CIs) from random-effects Weibull models. Results:A total of 20 113 patients, including 6369 (31.7%) patients from 10 programmes with access to viral load monitoring, were analysed; 576 patients (2.9%) switched. Low CD4 cell counts at ART initiation were associated with switching in all programmes. Median time to switching was 16.3 months [interquartile range (IQR) 10.1–26.6] in programmes with viral load monitoring and 21.8 months (IQR 14.0–21.8) in programmes without viral load monitoring (P < 0.001). Median CD4 cell counts at switching were 161 cells/μl (IQR 77–265) in programmes with viral load monitoring and 102 cells/μl (44–181) in programmes without viral load monitoring (P < 0.001). Switching was more common in programmes with viral load monitoring during months 7–18 after starting ART (aHR 1.38; 95% CI 0.97–1.98), similar during months 19–30 (aHR 0.97; 95% CI 0.58–1.60) and less common during months 31–42 (aHR 0.29; 95% CI 0.11–0.79). Conclusion:In resource-limited settings, switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with viral load monitoring compared with programmes without viral load monitoring.

Discordant Responses to Potent Antiretroviral Treatment in Previously Naive HIV-1-Infected Adults Initiating Treatment in Resource-Constrained Countries The Antiretroviral Therapy in Low-Income Countries (ART-LINC) Collaboration

Objectives:To assess the frequency of and risk factors for discordant responses at 6 months on highly active antiretroviral therapy (HAART) in previously treatment-naive HIV patients from resource-limited countries. Methods:The Antiretroviral Therapy in Low-Income Countries Collaboration is a network of clinics providing care and treatment to HIV-infected patients in Africa, Latin America, and Asia. Patients who initiated therapy between 1996 and 2004, were aged 16 years or older, and had a baseline CD4 cell count were included in this analysis. Responses were defined based on plasma viral load (PVL) and CD4 cell count at 6 months as complete virologic and immunologic (VR+IR+), virologic only (VR+IR−), immunologic only (VR−IR+), and nonresponse (VR−IR−). Multinomial logistic regression was used to assess the association between therapy responses and clinical and demographic variables. Results:Of the 3111 patients eligible for analysis, 1914 had available information at 6 months of therapy: 1074 (56.1%) were VR+IR+, 364 (19.0%) were VR+IR−, 283 (14.8%) were (VR−IR+), and 193 (10.1%) were VR−IR−. Compared with complete responders, virologic-only responders were older, had a higher baseline CD4 cell count, had a lower baseline PVL, and were more likely to have received a nonstandard HAART regimen; immunologic-only responders were younger, had a lower baseline CD4 cell count, had a higher baseline PVL, and were more likely to have received a protease inhibitor-based regimen. Conclusions:The frequency of and risk factors for discordant responses were comparable to those observed in developed countries. Longer follow-up is needed to assess the long-term impact of discordant responses on mortality in these resource-limited settings.

Tuberculosis after initiation of antiretroviral therapy in low-income and high-income countries

We examined the incidence of and risk factors for tuberculosis during the first year of highly active antiretroviral therapy in low-income (4540 patients) and high-income (22,217 patients) countries. Although incidence was much higher in low-income countries, the reduction in the incidence of tuberculosis associated with highly active antiretroviral therapy was similar: the rate ratio for months 7-12 versus months 1-3 was 0.48 (95% confidence interval, 0.36-0.64) in low-income countries and 0.36 (95% confidence interval, 0.26-0.50) in high-income countries. A low CD4 cell count at the start of therapy was the most important risk factor in both settings.

Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy

Objectives  To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment.

Epidemiologic and molecular characterization of human immunodeficiency virus type 1 in Southern Brazil

HIV subtype C is the most prevalent subtype in the world. Despite its recent expansion in Brazil, HIV-1C already prevails in the southernmost state of Brazil, Rio Grande do Sul. This unique HIV epidemiology has prompted us to characterize that population. Seventy-seven HIV-1–infected subjects attending the largest HIV/AIDS clinic of the state had the protease and reverse transcriptase (RT) genes of their virus subtyped and genotyped. When subtype-specific infections were plotted according to year of diagnosis, the prevalence of subtype C was shown to increase over the last 18 years of the epidemic, along with a concomitant decrease of subtype B. Comparison of subtype C–infected treated and untreated subjects revealed amino acid differences in protease and RT, especially in the RT mutation D/G123S. The overall analysis of drug resistance mutations in viruses from treated subjects has highlighted some associations between subtypes and particular mutations, such as V82A/F/T/S in protease and subtype F1 and M41L and L210W in RT and subtype B. The characterization of this important population, which is one of a few in the developing world where a large number of HIV-1C–infected subjects are under antiretroviral treatment, underscores its potential usefulness in clinical, treatment, and vaccine trials in Brazil.