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HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1-infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points ( P = 0.37) but were significantly lower in individuals with below-median viral load set points ( P = 0.03), and there was a trend of correlation between lower replication capacities and lower rates of CD4 decline ( P = 0.09). Overall, the proportion of host HLA-specific Gag polymorphisms in or adjacent to epitopes was negatively associated with replication capacities ( P = 0.04), but host HLA-B-specific polymorphisms were associated with higher viral load set points ( P = 0.01). Further, polymorphisms associated with host-specific protective HLA alleles were linked with higher viral load set points ( P = 0.03). These data suggest that transmission or early HLA-driven selection of Gag polymorphisms results in reduced early cytotoxic T-lymphocyte (CTL) responses and higher viral load set points. In support of the former, 46% of individuals with nonprotective alleles harbored a Gag polymorphism exclusively associated with a protective HLA allele, indicating a high rate of their transmission in sub-Saharan Africa. Overall, HIV disease progression is likely to be affected by the ability to mount effective Gag CTL responses as well as the replication capacity of the transmitted virus.

The mechanisms underlying HIV-1 control by protective HLA class I alleles are not fully understood and could involve selection of escape mutations in functionally important Gag epitopes resulting in fitness costs. This study was undertaken to investigate, at the population level, the impact of HLA-mediated immune pressure in Gag on viral fitness and its influence on HIV-1 pathogenesis. Replication capacities of 406 recombinant viruses encoding plasma-derived Gag-protease from patients chronically infected with HIV-1 subtype C were assayed in an HIV-1-inducible green fluorescent protein reporter cell line. Viral replication capacities varied significantly with respect to the specific HLA-B alleles expressed by the patient, and protective HLA-B alleles, most notably HLA-B*81, were associated with lower replication capacities. HLA-associated mutations at low-entropy sites, especially the HLA-B*81-associated 186S mutation in the TL9 epitope, were associated with lower replication capacities. Most mutations linked to alterations in replication capacity in the conserved p24 region decreased replication capacity, while most in the highly variable p17 region increased replication capacity. Replication capacity also correlated positively with baseline viral load and negatively with baseline CD4 count but did not correlate with the subsequent rate of CD4 decline. In conclusion, there is evidence that protective HLA alleles, in particular HLA-B*81, significantly influence Gag-protease function by driving sequence changes in Gag and that conserved regions of Gag should be included in a vaccine aiming to drive HIV-1 toward a less fit state. However, the long-term clinical benefit of immune-driven fitness costs is uncertain given the lack of correlation with longitudinal markers of disease progression.

BACKGROUND: Interleukin-10 (IL-10) is a potent immunoregulatory cytokine. IL-10-promoter polymorphisms have been shown to affect human immunodeficiency virus type 1 (HIV-1) clinical outcomes but the underlying mechanisms are poorly understood. METHODS: We investigated the relationship between IL-10-promoter variants, plasma cytokine levels, immune responses and markers of disease outcome in antiretroviral-naïve HIV-1 chronically infected individuals from South Africa. Two IL-10-promoter single nucleotide polymorphisms (SNPs) were genotyped in 451 participants. Baseline plasma levels of select cytokines were measured for 112 individuals. Viral load, CD4(+) T-cell counts and HIV-1-specific interferon-gamma CD8(+) T-cell immune responses were measured at baseline. CD4(+) T-cell counts were measured longitudinally and rates of CD4(+) T-cell decline computed for 300 study subjects. RESULTS: The minor IL-10-1082G and -592A variants occurred at frequencies of 0.31 and 0.34, respectively. The -592AA genotype associated significantly with attenuated loss of CD4(+) T cells (P = .0496). Individuals possessing -1082GG had significantly higher IL-10 levels compared to -1082AA/AG (P = .0006). The -592AA genotype was associated with greater breadth of virus-specific CD8(+) T-cell responses compared to CC and CA (P = .002 and .004 respectively). CONCLUSIONS: IL-10-promoter variants may influence the rate of HIV-1 disease progression by regulating IL-10 levels and the breadth of CD8(+) T-cell immune responses.

BACKGROUND: World Health Organization guidelines for antiretroviral treatment (ART) in resource-limited settings recommend either stavudine or tenofovir as part of initial therapy. We evaluated the clinical outcomes and cost-effectiveness of first-line ART using tenofovir in India compared with current practice using stavudine or zidovudine. METHODS: We used a state-transition model of human immunodeficiency virus (HIV) disease to examine strategies using different nucleoside reverse-transcriptase inhibitors combined with lamivudine and nevirapine compared with no ART: (1) stavudine (2) stavudine with substitution by zidovudine after 6 months (3) zidovudine and (4) tenofovir. Data were from the Y. R. Gaitonde Centre for AIDS Research and Education in Chennai India and published studies. Results. Discounted mean per person survival was 36.9 months (40.2 months undiscounted) with no ART 115.5 months (145.3) with stavudine-containing ART 115.7 months (145.6) with stavudine and 6-month zidovudine substitution 115.8 months (145.6) with zidovudine-containing ART and 125.8 months (162.0) with initial tenofovir. Discounted lifetime medical costs were $610 with no ART and ranged from $5580 with stavudine-containing ART to $5720 with zidovudine-containing ART. Initial tenofovir had an incremental cost-effectiveness ratio of $670 per year of life saved compared with no ART and was more economically efficient than the other regimens. RESULTS: were most sensitive to variations in the costs of first-line tenofovir access to additional ART after treatment failure and quality of life adjustment. CONCLUSIONS: Using tenofovir as part of first-line ART in India will improve survival is cost-effective by international standards and should be considered for initial therapy for HIV-infected patients in India.

To examine the loss to care and mortality rates before starting antiretroviral therapy (ART) among ART eligible HIV-infected patients in Durban, South Africa.Retrospective cohort study.We reviewed data from ART eligible adults (or = 18 years) at an urban HIV clinic that charges a monthly fee from July to December 2006. ART eligibility was based on CD4 countor = 200 cells per microliter or clinical criteria and a psychosocial assessment. Patients who did not start ART and were lost within 3 months were phoned. Correlates of loss to care were evaluated using logistic regression.During the study period, 501 patients registered for ART training. Mean time from initial CD4 count to first ART training was 3.6 months (interquartile range 2.3-3.9 months). Four hundred eight patients (81.4%) were in care and on ART at 3-month follow-up, and 11 (2.2%) were in care but had not initiated ART. Eighty-two ART eligible patients (16.4%) were lost before ART initiation. Of these, 28 (34.1%) had died; two thirds of deaths occurred before or within 2 months after the first ART training. Despite multiple attempts, 32 patients (39%) were unreachable by phone. Lower baseline CD4 counts (or = 100 cells/microL) and unemployment were independently associated with being lost.Loss to care and death occur frequently before starting ART at an HIV clinic in Durban, South Africa. This delay from CD4 count to ART training, even among those with the lowest CD4 counts, highlights the need for interventions that improve linkage to care and prioritize ART initiation for those with low baseline CD4 counts.

In the 2 decades since scientists identified HIV, it has arguably become the greatest threat to life and prosperity in the developing world. Sub-Saharan Africa, home to 25.8 million of the 40 million people infected with HIV worldwide, remains the most harshly affected.1 South Africa, with a population of 44 million, has an estimated 5.3 million citizens infected, with prevalence levels increasing in all age groups.1,2 The severity of the HIV epidemic led the South African government to approve and implement a plan for universal access to antiretroviral (ARV) treatment in 2003.3,4 This prompted the expansion of traditional HIV voluntary counseling and testing (VCT) centers to identify HIV-infected people and facilitate their entry into care. In a sample of clinics and community health centers in South Africa, more than 50% of primary health care facilities provide VCT.5 Only 1 in 5 South Africans who are even aware of VCT has been tested for HIV infection, however.6,7 Proposed reasons for poor rates of VCT participation in South Africa include lack of confidentiality, fear of stigmatization by being singled out, inability to enter treatment if infected, and inconvenience of testing sites.6,8,9 Even in the United States, where HIV prevalence is a small fraction of what it is in Africa, the Centers for Disease Control and Prevention now recommend a screening approach: making HIV testing a routine part of medical care for people aged 13 to 64 years.10–12 The rationale for routine testing rather than risk-based testing based on physician referral to VCT is to decrease barriers to testing, to decrease risk-taking behavior among infected individuals, and to identify HIV-infected individuals earlier in their disease course so as to provide maximal benefits of therapy.10,13–15 Routine testing in the United States has improved acceptance of HIV testing in prenatal clinics,16 inpatient wards,17 emergency departments,18 and urgent care clinics.19–22 Routine health provider–initiated testing for all people who interact with the health care system is also supported by the World Health Organization (WHO).23 Given the enormous stigma surrounding HIV-infected individuals, it is not clear whether broader testing in resource-limited settings would be accepted more readily than VCT by patients seeking medical care for complaints potentially unrelated to underlying HIV infection.6 Few studies have explored the impact of routine testing in African health care settings on patient uptake, stage at diagnosis, linkage to care, and programmatic costs.24 Our objective was to compare the HIV testing process before and after establishing a routine HIV testing program at the McCord Hospital outpatient department (OPD) in Durban, South Africa.

India has more than 5.7 million people infected with human immunodeficiency virus (HIV). In 2004, the Indian government began providing antiretroviral therapy (ART), and there are now an estimated 56 500 people receiving ART.To project the life expectancy, cost, and cost-effectiveness associated with different strategies for using ART in India, to inform treatment programs.We utilized an HIV disease simulation model, incorporating data on natural history, treatment efficacy, and costs of care from India. Input parameters for the simulated cohort included mean age 32.6 years and mean CD4 count 318 cells/microl (SD 291 cells/microl). We examined different criteria for starting and stopping ART with a first-line regimen of stavudine/lamivudine/nevirapine, and the impact of a second-line protease-inhibitor-based regimen. Cost-effectiveness in US dollars per year of life saved (US$/YLS) was compared incrementally among alternative starting, sequencing, and stopping criteria.Discounted (undiscounted) mean survival ranged from 34.5 (37.5) months with no ART to 64.7 (73.6) months with one line of therapy initiated at CD4350 cells/microl, to 88.9 (106.5) months with two lines of therapy initiated at CD4350 cells/microl. Lifetime medical costs ranged from US$530 (no ART) to US$5430 (two ART regimens) per person. With one line of therapy, the incremental cost-effectiveness ratios ranged from US$430/YLS to US$550/YLS as the CD4 starting criterion was increased from CD4250 cells/microl to350 cells/microl. Use of two lines of therapy had an incremental cost-effectiveness ratio of US$1880/YLS compared with the use of first-line therapy alone. Results were sensitive to the costs of second-line therapy and criteria for stopping therapy.In India, antiretroviral therapy will lead to major survival benefits and is cost-effective by World Health Organization criteria. The availability of second-line regimens will further increase survival, but their cost-effectiveness depends on their relative cost compared with first-line regimens.

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.

OBJECTIVE: To quantify the impact of tuberculosis (TB) co-infection on death and loss to follow-up (LTFU) 12 months after entry into an ART program. DESIGN: Prospective intervention study. METHODS: From May 2007 to 2008 patients undergoing pre-ART training in Durban South Africa were screened for pulmonary TB using mycobacterial culture. Subjects missing appointments for >3 months were phoned. Patients who could not be reached were considered LTFU. Deaths were ascertained by report from family members. We used the Kaplan-Meier method to estimate time to LTFU or death for 3 groups at enrollment as follows: (1) newly diagnosed with TB by sputum culture; (2) on TB treatment (ie previously diagnosed); and (3) TB free. We evaluated the role of TB on mortality and LTFU using Cox proportional hazards models. RESULTS: Nine hundred fifty-one HIV-infected subjects were enrolled; 59% were female and median baseline CD4 count was 90 cells per microliter (IQR: 41-148 cells/muL). One hundred forty-four (15%) were newly diagnosed with TB by sputum culture; an additional 199 (21%) were already on TB treatment. By 12 months 26% newly diagnosed with TB at enrollment died or were LTFU compared with 19% already on TB treatment and 14% who were TB free (P = 0.001). Controlling for age sex smoking CD4 and opportunistic infection history subjects newly diagnosed with pulmonary TB were 76% more likely to die or be LTFU (hazard ratio: 1.76 95% confidence interval: 1.20 to 2.60) than those without TB. CONCLUSIONS: HIV/TB co-infected individuals are more likely to die or be LTFU within 12 months of ART clinic entry in South Africa. These patients require intensive follow-up during ART initiation.

Background. Faith-based organisations have expanded antiretroviral therapy (ART) in community clinics across South Africa. Loss to follow-up (LTFU), however, limits the potential individual and population treatment benefits and optimal care. Objective. To identify patient characteristics associated with LTFU 6 months after starting ART in a large community clinic. Methods. Patients initiating ART between April 2004 and October 2006 in one South African Catholic Bishops’ Conference HIV treatment clinic who had at least one follow-up visit were included and routinely monitored every 6 months after ART initiation. Standardised instruments were used to collect data. Rates of LTFU over time were estimated by the Kaplan-Meier method. The Cox proportional hazard regression examined the impact of age, baseline CD4 count, baseline HIV RNA, gender and pregnancy status on LTFU. Results. Data from 925 patients (age >14 years, median age 36 years, 70% female, of whom 16% were pregnant) were included: 51 (6%) were lost to follow-up 6 months after ART initiation. Younger age (≤30 years) (hazard ratio (HR) 2.14, 95% confidence interval (CI) 1.05 - 4.38) and pregnancy for women (HR 3.75, 95% CI 1.53 - 9.16) were significantly associated with higher LTFU rates. When stratified by baseline CD4 count, gender and pregnancy status, pregnant women with lower baseline CD4 counts (≤200 cells/ μl) had 6.06 times the hazard (95% CI 2.20 - 16.71) of LTFU at 6 months compared with men. Conclusions. HIV-infected pregnant women initiating ART were significantly more likely to be lost to follow-up in a community clinic in South Africa. Urgent interventions to successfully retain pregnant women in care are needed.

BACKGROUND: The World Health Organization (WHO) recommends cough as the trigger for tuberculosis screening in human immunodeficiency virus (HIV)-infected patients with acid-fast bacillus (AFB) smear as the initial diagnostic test. Our objective was to assess the yield and cost of a more intensive tuberculosis screening in HIV-infected patients starting antiretroviral therapy (ART) in Durban South Africa. METHODS: We prospectively enrolled adults regardless of tuberculosis signs/symptoms who were undergoing ART training from May 2007 to May 2008. After the symptom screen patients expectorated sputum for AFB smear tuberculosis polymerase chain reaction (PCR) and mycobacterial culture. Sensitivity and specificity of different symptoms and tests alone and in combination were compared with the reference standard of 6-week tuberculosis culture results. Program costs included personnel materials and cultures. RESULTS: Of 1035 subjects 487 (59%) were female; median CD4 cell count was 100 cells/microL. A total of 210 subjects (20%) were receiving tuberculosis treatment and were excluded. Of the remaining 825 subjects 158 (19%) had positive sputum cultures of whom 14 (9%) had a positive AFB smear and 82 (52%) reported cough. The combination of cough other symptoms AFB smear and chest radiograph had 93% sensitivity (95% confidence interval 88%-97%) and 15% specificity (95% confidence interval 13%-18%). The incremental cost of intensive screening including culture was $360 per additional tuberculosis case identified. CONCLUSIONS: Nearly 20% of patients starting ART in Durban South Africa had undiagnosed culture-positive pulmonary tuberculosis. Despite WHO recommendations neither cough nor AFB smear were adequately sensitive for screening. Tuberculosis sputum cultures should be performed before ART initiation regardless of symptoms in areas with a high prevalence of HIV and tuberculosis.

HIV/hepatitis C virus (HCV) co-infection places a growing burden on the HIV/AIDS care delivery system. Evidence-based estimates of health services utilization among HIV/HCV co-infected patients can inform efficient planning. We analyzed data from the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort to estimate resource utilization and disability among HIV/HCV co-infected patients and compare them to rates seen in HIV mono-infected patients. The analysis included HIV-infected subjects enrolled in the ALLRT cohort between 2000 and 2007 who had at least one CD4 count measured and completed at least one resource utilization data collection form (N = 3143). Primary outcomes included the relative risk of hospital nights, emergency department (ED) visits, and disability days for HIV/HCV co-infected vs HIV mono-infected subjects. When controlling for age, sex, race, history of AIDS-defining events, current CD4 count and current HIV RNA, the relative risk of hospitalization, ED visits, and disability days for subjects with HIV/HCV co-infection compared to those with HIV mono-infection were 1.8 (95% CI: 1.3-2.5), 1.7 (95% CI: 1.4-2.1), and 1.6 (95% CI: 1.3-1.9) respectively. Programs serving HIV/HCV co-infected patients can expect approximately 70% higher rates of utilization than expected from a similar cohort of HIV mono-infected patients.

The results of international clinical trials that are assessing when to initiate antiretroviral therapy (ART) will not be available for several years.To inform HIV treatment decisions about the optimal CD4 threshold at which to initiate ART in South Africa while awaiting the results of these trials.Cost-effectiveness analysis by using a computer simulation model of HIV disease.Published data from randomized trials and observational cohorts in South Africa.HIV-infected patients in South Africa.5-year and lifetime.Modified societal.No treatment, ART initiated at a CD4 count less than 0.250 x 10(9) cells/L, and ART initiated at a CD4 count less than 0.350 x 10(9) cells/L.Morbidity, mortality, life expectancy, medical costs, and cost-effectiveness.If 10% to 100% of HIV-infected patients are identified and linked to care, a CD4 count threshold for ART initiation of 0.350 x 10(9) cells/L would reduce severe opportunistic diseases by 22,000 to 221,000 and deaths by 25,000 to 253,000 during the next 5 years compared with ART initiation at 0.250 x 10(9) cells/L; cost increases would range from $142 million (10%) to $1.4 billion (100%). Either ART initiation strategy would increase long-term survival by at least 7.9 years, with a mean per-person life expectancy of 3.8 years with no ART and 12.5 years with an initiation threshold of 0.350 x 10(9) cells/L. Compared with an initiation threshold of 0.250 x 10(9) cells/L, a threshold of 0.350 x 10(9) cells/L has an incremental cost-effectiveness ratio of $1200 per year of life saved.Initiating ART at a CD4 count less than 0.350 x 10(9) cells/L would remain cost-effective over the next 5 years even if the probability that the trial would demonstrate the superiority of earlier therapy is as low as 17%.This model does not consider the possible benefits of initiating ART at a CD4 count greater than 0.350 x 10(9) cells/L or of reduced HIV transmission.Earlier initiation of ART in South Africa will probably reduce morbidity and mortality, improve long-term survival, and be cost-effective. While awaiting trial results, treatment guidelines should be liberalized to allow initiation at CD4 counts less than 0.350 x 10(9) cells/L, earlier than is currently recommended.National Institute of Allergy and Infectious Diseases and the Doris Duke Charitable Foundation.

Background The combination of tenofovir and emtricitabine shows promise as HIV preexposure prophylaxis (PrEP). We sought to forecast clinical, epidemiologic, and economic outcomes of PrEP, taking into account uncertainties regarding efficacy, the risks of developing drug resistance and toxicity, behavioral disinhibition, and drug costs. Methods We adapted a computer simulation of HIV acquisition, detection, and care to model PrEP among men who have sex with men and are at high risk of HIV infection (i.e., 1.6% mean annual incidence of HIV infection) in the United States. Base-case assumptions included 50% PrEP efficacy and monthly tenofovir-emtricitabine costs of $753. We used sensitivity analyses to examine the stability of results and to identify critical input parameters. Results In a cohort with a mean age of 34 years, PrEP reduced lifetime HIV infection risk from 44% to 25% and increased mean life expectancy from 39.9 to 40.7 years (21.7 to 22.2 discounted quality-adjusted life-years). Discounted mean lifetime treatment costs increased from $81,100 to $232,700 per person, indicating an incremental cost-effectiveness ratio of $298,000 per quality-adjusted life-year gained. Markedly larger reductions in lifetime infection risk (from 44% to 6%) were observed with the assumption of greater (90%) PrEP efficacy. More-favorable incremental cost-effectiveness ratios were obtained by targeting younger populations with a higher incidence of infection and by improvements in the efficacy and cost of PrEP. Conclusions PrEP could substantially reduce the incidence of HIV transmission in populations at high risk of HIV infection in the United States. Although it is unlikely to confer sufficient benefits to justify the current costs of tenofovir-emtricitabine, price reductions and/or increases in efficacy could make PrEP a cost-effective option in younger populations or populations at higher risk of infection. Given recent disappointments in HIV infection prevention and vaccine development, additional study of PrEP-based HIV prevention is warranted.

Background Routine HIV testing is increasingly recommended in resource-limited settings. Our objective was to evaluate factors associated with a new diagnosis of HIV infection in a routine HIV testing programme in South Africa. Methods We established a routine HIV testing programme in an out-patient department in Durban, South Africa. All registered adults were offered a rapid HIV test; we surveyed a sample of tested patients. Results During the 12-week study, 1414 adults accepted HIV testing. Of those, 463 (32.7%) were HIV-infected. Seven hundred and twenty (50.9%) were surveyed. Compared with married women, unmarried men were at the highest risk of HIV [odds ratio (OR) 6.84; 95% confidence interval (CI) 3.45–23.55], followed by unmarried women (OR 5.90; 95% CI 3.25–10.70) and married men (OR 4.00; 95% CI 2.04–7.83). Age 30–39 years (compared with ≥50 years; OR 5.10; 95% CI 2.86–9.09), no prior HIV test (OR 1.45; 95% CI 1.07–2.27) and an imperfect HIV knowledge score (OR 2.32; 95% CI 1.24–4.35) were also associated with HIV infection. Conclusion In a routine HIV testing programme in South Africa, rates of previously undiagnosed HIV were highest among men, young and unmarried patients, and those with poorer HIV knowledge. Better interventions are needed to improve HIV knowledge and decrease HIV risk behaviour.

South Africa has one of the largest burdens of HIV disease in the world, with an estimated 4.9 − 6.1 million people infected and a reported prevalence of 18.8% in adults 15−49 years old [1]. In 2007, the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimated that 1,000,000 people in South Africa required antiretroviral therapy (ART) [2]. The number of patients with access to ART is steadily increasing, largely as a result of funding from the South African government itself, as well as strategic assistance from the US President's Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) [3–5]. Treatment efforts have been accompanied by a national AIDS plan for drug distribution, creation of a more comprehensive health care infrastructure, and establishment of treatment guidelines [6]. Even with these remarkable expansions in capacity, however, the enormity of the epidemic continues to overwhelm the treatment systems; by the end of 2006, ART was reaching fewer than 33% of eligible patients in South Africa [7]. For development of health policy, it is useful to quantify the potential consequences of disease outcomes under different treatment and practice scenarios [8]. To this end, our objective was to project alternative ART rollout scenarios over the next several years in South Africa. The goals were to forecast the number of lives lost while awaiting needed therapy, to estimate the number of people both in and out of care, and to project when and whether HIV treatment needs would be fully met. These estimates can be used to inform decisions regarding the life-saving value of alternative treatment expansion scenarios in South Africa, as well as in other developing countries.

Background Studies in developed countries have shown highly active antiretroviral therapy (HAART) decreases incidence of severe opportunistic diseases (ODs) in HIV-infected patients beyond that which is expected from changes in CD4+T-cell count. Objective To estimate the independent impact of HAART on reducing ODs and mortality in Côte d'Ivoire. Methods Within two longitudinal studies of HIV-infected adults (1996–2003), we identified time on ‘cotrimoxazole alone’ and ‘HAART plus cotrimoxazole’. WHO stage 3–4 defining events and severe malaria were divided into those preventable and not preventable with cotrimoxazole. Incidence of ODs by CD4 count stratum was estimated using incidence density analysis. CD4+ T-cell count at time of OD was estimated using linear interpolation. Using Poisson regression, we estimated the effect of HAART on OD incidence and mortality by CD4 count stratum. Results Totals of 446 and 135 adults were followed during 6,216 and 3,412 person-months in the cotrimoxazole alone and HAART plus cotrimoxazole periods, respectively. There was a CD4+ T-cell-independent risk reduction for ODs and mortality during the HAART plus cotrimoxazole period compared with cotrimoxazole alone, which varied by time on HAART, CD4 count stratum and OD type. It was mainly seen after 6 months on HAART and for ODs not preventable by cotrimoxazole. The HAART effect differed significantly by CD4 count stratum ( P=0.02), but was significant in all strata after 6 months on HAART. Conclusions In these sub-Saharan African adults, HAART initiation reduced ODs and mortality beyond that which was expected through the HAART-induced CD4+ T-cell increase. Further studies should examine practical implications of this independent ‘HAART effect’ on clinical outcomes in patients on HAART.

CD4 lymphocyte count is an important surrogate marker of HIV disease progression, but it is often unavailable at the time of clinical events. We analysed data from the Cotrame cohort (1999–2004) and the Trivacan Structured Treatment Interruption trial (2002–2005) to estimate the incidence of opportunistic infections and death within specific CD4 strata in HIV-infected patients receiving highly active antiretroviral therapy (HAART) in sub-Saharan Africa. We used three methods of CD4 modelling: the first assumed that CD4 cell count remained constant until the next measurement; the second assumed that it changed immediately to the level of the subsequent measurement; and the third assumed that it followed a linear function between two consecutive CD4 measurements. The cohort used in this analysis consisted of 981 patients. The incidence rates of opportunistic infections were highest in the lower CD4 strata and decreased in the higher CD4 count strata. The incidence rates of mild opportunistic infections and severe bacterial infections, however, remained high in the highest CD4 stratum. Although all confidence intervals overlapped among the three methods, the incidence rate estimates showed differences of up to 74% in the lowest CD4 stratum. Different methods of estimating CD4 counts at the time of clinical events led to minor differences in incidence rates, except in the CD4 stratum

BackgroundModel-based analyses, conducted within a decision analytic framework, provide a systematic way to combine information about the natural history of disease and effectiveness of clinical management strategies with demographic and epidemiological characteristics of the population. Among the challenges with disease-specific modeling include the need to identify influential assumptions and to assess the face validity and internal consistency of the model.Methods and findingsWe describe a series of exercises involved in adapting a computer-based simulation model of HIV disease to the Women's Interagency HIV Study (WIHS) cohort and assess model performance as we re-parameterized the model to address policy questions in the U.S. relevant to HIV-infected women using data from the WIHS. Empiric calibration targets included 24-month survival curves stratified by treatment status and CD4 cell count. The most influential assumptions in untreated women included chronic HIV-associated mortality following an opportunistic infection, and in treated women, the 'clinical effectiveness' of HAART and the ability of HAART to prevent HIV complications independent of virologic suppression. Good-fitting parameter sets required reductions in the clinical effectiveness of 1st and 2nd line HAART and improvements in 3rd and 4th line regimens. Projected rates of treatment regimen switching using the calibrated cohort-specific model closely approximated independent analyses published using data from the WIHS.ConclusionsThe model demonstrated good internal consistency and face validity, and supported cohort heterogeneities that have been reported in the literature. Iterative assessment of model performance can provide information about the relative influence of uncertain assumptions and provide insight into heterogeneities within and between cohorts. Description of calibration exercises can enhance the transparency of disease-specific models.