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1.  Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind placebo-controlled trial 
Lancet  2014;384(9944):682-690.
Background
Antiretroviral therapy (ART) reduces the risk of tuberculosis, but the incidence still exceeds that in HIV-uninfected people. Isoniazid preventive therapy (IPT), which decreases the risk of tuberculosis in people not on ART, may offer additional protection.
Methods
Pragmatic randomized double-blind placebo-controlled trial to evaluate the effect of 12 months IPT among participants established on or newly starting ART, in Khayelitsha, South Africa (NCT00463086, Lancet D-09-02885). Tuberculosis was excluded at screening by sputum culture. Incident tuberculosis was the primary endpoint.
Findings
1,329 participants contributed 3,227 person-years (PY) of follow up in the modified intention-to-treat analysis; 662 on IPT and 667 on placebo. There were 95 incident tuberculosis cases: 2.3 (95%CI 1.6-3.1) versus 3.6 (95%CI 2.8-4.7) per 100 PY in the IPT and placebo arms respectively (hazard ratio 0.63, 95%CI 0.41-0.94). Study drug was discontinued due to grade 3 or 4 raised ALT in 19/662 in the IPT and 10/667 in the placebo arm, risk ratio=1.9 (95%CI 0.90-4.09). In secondary analyses, there was no evidence that the effect of IPT was restricted to those who were positive on tuberculin skin test (TST) or interferon gamma release assay (IGRA): adjusted hazard ratio for those with negative tests 0.43 (95%CI 0.21-0.86) and 0.43 (95%CI 0.20-0.96); for positive tests 0.86 (95%CI 0.37-2.00) and 0.55 (95%CI 0.26-1.24) respectively. No all cause mortality benefit of IPT was demonstrated
Interpretation
IPT reduced the incidence of tuberculosis in HIV-infected individuals on ART. In this high incidence setting, individuals on ART who have TST or IGRA negative results may also benefit from IPT. IPT can easily be implemented in ART clinics.
doi:10.1016/S0140-6736(14)60162-8
PMCID: PMC4233253  PMID: 24835842
2.  Patterns of HIV, TB, and non-communicable disease multi-morbidity in peri-urban South Africa- a cross sectional study 
Background
Many low and middle-income countries are experiencing colliding epidemics of chronic infectious (ID) and non-communicable diseases (NCD). As a result, the prevalence of multiple morbidities (MM) is rising.
Methods
We conducted a study to describe the epidemiology of MM in a primary care clinic in Khayelitsha. Adults with at least one of HIV, tuberculosis (TB), diabetes (DM), and hypertension (HPT) were identified between Sept 2012-May 2013 on electronic databases. Using unique patient identifiers, drugs prescribed across all facilities in the province were linked to each patient and each drug class assigned a condition.
Results
These 4 diseases accounted for 45% of all prescription visits. Among 14364 chronic disease patients, HPT was the most common morbidity (65%). 22.6% of patients had MM, with an increasing prevalence with age; and a high prevalence among younger antiretroviral therapy (ART) patients (26% and 30% in 18-35 yr and 36–45 year age groups respectively). Among these younger ART patients with MM, HPT and DM prevalence was higher than in those not on ART.
Conclusions
We highlight the co-existence of multiple ID and NCD. This presents both challenges (increasing complexity and the impact on health services, providers and patients), and opportunities for chronic diseases screening in a population linked to care. It also necessitates re-thinking of models of health care delivery and requires policy interventions to integrate and coordinate management of co-morbid chronic diseases.
doi:10.1186/s12879-015-0750-1
PMCID: PMC4300166  PMID: 25595711
HIV; Tuberculosis; Hypertension; Diabetes; Multimorbidity
3.  Tenofovir or zidovudine in second-line antiretroviral therapy after stavudine failure in southern Africa 
Antiviral therapy  2013;19(5):521-525.
Background
There is debate over using tenofovir or zidovudine alongside lamivudine in second-line antiretroviral therapy (ART) following stavudine failure. We analyzed outcomes in cohorts from South Africa, Zambia and Zimbabwe
Methods
Patients aged ≥16 years who switched from a first-line regimen including stavudine to a ritonavir-boosted lopinavir-based second-line regimen with lamivudine or emtricitabine and zidovudine or tenofovir in seven ART programs in southern Africa were included. We estimated the causal effect of receiving tenofovir or zidovudine on mortality and virological failure using Cox proportional hazards marginal structural models. Its parameters were estimated using inverse probability of treatment weights. Baseline characteristics were age, sex, calendar year and country. CD4 cell count, creatinine and hemoglobin levels were included as time-dependent confounders.
Results
1,256 patients on second-line ART, including 958 on tenofovir, were analyzed. Patients on tenofovir were more likely to have switched to second-line ART in recent years, spent more time on first-line ART (33 vs. 24 months) and had lower CD4 cell counts (172 vs. 341 cells/μl) at initiation of second-line ART. The adjusted hazard ratio comparing tenofovir with zidovudine was 1.00 (95% confidence interval 0.59-1.68) for virologic failure and 1.40 (0.57-3.41) for death.
Conclusions
We did not find any difference in treatment outcomes between patients on tenofovir or zidovudine; however, the precision of our estimates was limited. There is an urgent need for randomized trials to inform second-line ART strategies in resource-limited settings.
doi:10.3851/IMP2710
PMCID: PMC4043936  PMID: 24296645
HIV infection; second-line ART; cohort studies; causal modeling; sub-Saharan Africa
4.  Mortality in Patients with HIV-1 Infection Starting Antiretroviral Therapy in South Africa, Europe, or North America: A Collaborative Analysis of Prospective Studies 
PLoS Medicine  2014;11(9):e1001718.
Analyzing survival in HIV treatment cohorts, Andrew Boulle and colleagues find mortality rates in South Africa comparable to or better than those in North America by 4 years after starting antiretroviral therapy.
Please see later in the article for the Editors' Summary
Background
High early mortality in patients with HIV-1 starting antiretroviral therapy (ART) in sub-Saharan Africa, compared to Europe and North America, is well documented. Longer-term comparisons between settings have been limited by poor ascertainment of mortality in high burden African settings. This study aimed to compare mortality up to four years on ART between South Africa, Europe, and North America.
Methods and Findings
Data from four South African cohorts in which patients lost to follow-up (LTF) could be linked to the national population register to determine vital status were combined with data from Europe and North America. Cumulative mortality, crude and adjusted (for characteristics at ART initiation) mortality rate ratios (relative to South Africa), and predicted mortality rates were described by region at 0–3, 3–6, 6–12, 12–24, and 24–48 months on ART for the period 2001–2010. Of the adults included (30,467 [South Africa], 29,727 [Europe], and 7,160 [North America]), 20,306 (67%), 9,961 (34%), and 824 (12%) were women. Patients began treatment with markedly more advanced disease in South Africa (median CD4 count 102, 213, and 172 cells/µl in South Africa, Europe, and North America, respectively). High early mortality after starting ART in South Africa occurred mainly in patients starting ART with CD4 count <50 cells/µl. Cumulative mortality at 4 years was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. Mortality was initially much lower in Europe and North America than South Africa, but the differences were reduced or reversed (North America) at longer durations on ART (adjusted rate ratios 0.46, 95% CI 0.37–0.58, and 1.62, 95% CI 1.27–2.05 between 24 and 48 months on ART comparing Europe and North America to South Africa). While bias due to under-ascertainment of mortality was minimised through death registry linkage, residual bias could still be present due to differing approaches to and frequency of linkage.
Conclusions
After accounting for under-ascertainment of mortality, with increasing duration on ART, the mortality rate on HIV treatment in South Africa declines to levels comparable to or below those described in participating North American cohorts, while substantially narrowing the differential with the European cohorts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has killed about 36 million people since the first recorded case of the disease in 1981, and a similar number of people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other serious infections. Early in the AIDS epidemic, HIV-positive people usually died within 10 years of becoming infected. In 1996, effective antiretroviral therapy (ART) became available and, for people living in high-income countries, HIV infection became a chronic condition. But ART was expensive, so HIV/AIDS remained largely untreated and fatal in resource-limited countries. Then, in 2003, the international community began to work towards achieving universal access to ART. By the end of 2012, nearly two-thirds of HIV-positive people (nearly 10 million individuals) living in low- and middle-income countries who were eligible for treatment because their CD4 cell count had fallen below 350/mm3 blood or because they had developed an AIDS-defining condition were receiving treatment.
Why Was This Study Done?
It is known that a larger proportion of HIV-positive patients starting ART die during the first year of treatment in sub-Saharan Africa than in Europe and North America. This difference arises in part because patients in resource-limited settings tend to have lower CD4 counts when they start treatment than patients in wealthy countries. However, the lack of reliable data on mortality (death) in resource-limited settings has made it hard to compare longer-term outcomes in different settings. Information on the long-term outcomes of HIV-positive patients receiving ART in resource-limited countries is needed to guide the development of appropriate health systems and treatment regimens in these settings. In this collaborative analysis of prospective cohort studies, the researchers compare mortality up to 4 years on ART in South Africa, Europe, and North America. A prospective cohort study follows a group of individuals over time to see whether differences in specific characteristics at the start of the study affect subsequent outcomes. A collaborative analysis combines individual patient data from several studies.
What Did the Researchers Do and Find?
The researchers combined data from four South Africa cohorts of HIV-positive patients starting ART included in the International Epidemiologic Databases to Evaluate AIDS South African (IeDEA-SA) collaboration with data from six North American cohorts and nine European cohorts included in the ART Cohort Collaboration (ART-CC). The South African cohorts were chosen because unusually for studies undertaken in countries in sub-Saharan Africa the vital status of patients (whether they had died) who had been lost to follow-up in these cohorts could be obtained from the national population register. Patients in South Africa began treatment with more advanced disease (indicated by a lower average CD4 count) than patients in Europe or North America. Notably, high early mortality after starting ART in South Africa occurred mainly in patients starting ART with a CD4 count below 50 cells/mm3. The cumulative mortality after 4 years of ART was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. After adjusting for patient characteristics at ART initiation, the mortality rate among patients beginning ART was initially lower in Europe and North American than in South Africa. However, although the adjusted mortality rate in Europe remained lower than the rate in South Africa, the rate in North America was higher than that in South Africa between 24 and 48 months on ART.
What Do These Findings Mean?
Although the linkage to national vital registration systems (databases of births and deaths) undertaken in this collaborative analysis is likely to have greatly reduced bias due to under-ascertainment of mortality, the accuracy of these findings may still be limited by differences in how this linkage was undertaken in different settings. Nevertheless, these findings suggest that mortality among HIV-infected patients receiving ART in South Africa, although initially higher than in Europe and North America, rapidly declines with increasing duration on ART and, after 4 years of treatment, approaches the rate seen in high-income settings. Intriguingly, these findings also highlight the relatively higher late mortality in North America compared to either Europe or South Africa, a result that needs to be investigated to explore the extent to which differences in mortality ascertainment, patient characteristics and comorbidities, or health systems and treatment regimens contribute to variations in outcomes among HIV-positive patients in various settings.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001718.
This study is further discussed in a PLOS Medicine Perspective by Agnes Binagwaho and colleagues
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on universal access to ART, on HIV and AIDS in sub-Saharan Africa, and on HIV and AIDS in South Africa (in English and Spanish)
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infections: recommendations for a public health approach are available
The 2013 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information about the International Epidemiologic Databases to Evaluate AIDS South African (IeDEA-SA) collaboration and about the ART Cohort Collaboration is available
Personal stories about living with HIV/AIDS are available through Avert, Nam/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001718
PMCID: PMC4159124  PMID: 25203931
5.  Impact of definitions of loss to follow-up (LTFU) in antiretroviral therapy program evaluation: variation in the definition can have an appreciable impact on estimated proportions of LTFU 
Journal of clinical epidemiology  2013;66(9):1006-1013.
Objective
To examine the impact of different definitions of loss to follow-up (LTFU) on estimates of program outcomes in cohort studies of patients on antiretroviral therapy (ART).
Study Design and Setting
We examined the impact of different definitions of LTFU using data from the International Epidemiological Databases to Evaluate AIDS—Southern Africa. The reference approach, Definition A, was compared with five alternative scenarios that differed in eligibility for analysis and the date assigned to the LTFU outcome. Kaplan–Meier estimates of LTFU were calculated up to 2 years after starting ART.
Results
Estimated cumulative LTFU were 14% and 22% at 12 and 24 months, respectively, using the reference approach. Differences in the proportion LTFU were reported in the alternative scenarios with 12-month estimates of LTFU varying by up to 39% compared with Definition A. Differences were largest when the date assigned to the LTFU outcome was 6 months after the date of last contact and when the site-specific definition of LTFU was used.
Conclusion
Variation in the definitions of LTFU within cohort analyses can have an appreciable impact on estimated proportions of LTFU over 2 years of follow-up. Use of a standardized definition of LTFU is needed to accurately measure program effectiveness and comparability between programs.
doi:10.1016/j.jclinepi.2013.03.013
PMCID: PMC3759810  PMID: 23774112
Antiretroviral therapy; Program outcomes; Loss to follow-up; Cohort; Retention; Survival analysis
6.  A comparison of linkage to HIV care after provider-initiated HIV testing and counselling (PITC) versus voluntary HIV counselling and testing (VCT) for patients with sexually transmitted infections in Cape Town, South Africa 
Background
We examined linkage to care for patients with sexually transmitted infection who were diagnosed HIV-positive via the provider-initiated HIV testing and counselling (PITC) approach, as compared to the voluntary counselling and testing (VCT) approach, as little is known about the impact of expanded testing strategies on linkage to care.
Methods
In a controlled trial on PITC (Cape Town, 2007), we compared HIV follow-up care for a nested cohort of 930 HIV-positive patients. We cross-referenced HIV testing and laboratory records to determine access to CD4 and viral load testing as primary outcomes. Secondary outcomes were HIV immune status and time taken to be linked to HIV care. Logistic regression was performed to analyse the difference between arms.
Results
There was no difference in the main outcomes of patients with a record of CD4 testing (69.9% in the intervention, 65.2% in control sites, OR 0.82 (CI: 0.44-1.51; p = 0.526) and viral load testing (14.9% intervention versus 10.9% control arm; OR 0.69 (CI: 0.42-1.12; p = 0.131). In the intervention arm, ART-eligible patients (based on low CD4 test result), accessed viral load testing approximately 2.5 months sooner than those in the control arm (214 days vs. 288 days, HR: 0.417, 95% CI: 0.221-0.784; p = 0.007).
Conclusion
The PITC intervention did not improve linkage to CD4 testing, but shortened the time to viral load testing for ART-eligible patients. Major gaps found in follow-up care across both arms, indicate the need for more effective linkage-to-HIV care strategies.
Trial registration
Current Controlled Trials ISRCTN93692532
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6963-14-350) contains supplementary material, which is available to authorized users.
doi:10.1186/1472-6963-14-350
PMCID: PMC4147183  PMID: 25134822
Routine HIV screening; Linkage to HIV care; Sexually transmitted infections; Controlled trial; South Africa
7.  CD4 count slope and mortality in HIV-infected patients on antiretroviral therapy: multi-cohort analysis from South Africa 
Background
In many resource-limited settings monitoring of combination antiretroviral therapy (cART) is based on the current CD4 count, with limited access to HIV RNA tests or laboratory diagnostics. We examined whether the CD4 count slope over 6 months could provide additional prognostic information.
Methods
We analyzed data from a large multi-cohort study in South Africa, where HIV RNA is routinely monitored. Adult HIV-positive patients initiating cART between 2003 and 2010 were included. Mortality was analyzed in Cox models; CD4 count slope by HIV RNA level was assessed using linear mixed models.
Results
44,829 patients (median age 35 years, 58% female, median CD4 count at cART initiation 116 cells/mm3) were followed-up for a median of 1.9 years, with 3,706 deaths. Mean CD4 count slopes per week ranged from 1.4 (95% CI: 1.2, 1.6) cells/mm3 when HIV RNA was <400 copies/mL to −0.32 (95% CI: −0.47, −0.18) cells/mm3 with >100,000 copies/mL. The association of CD4 slope with mortality depended on current CD4 count: the adjusted hazard ratio (aHRs) comparing a >25% increase over 6 months with a >25% decrease was 0.68 (95% CI 0.58-0.79) at <100 cells/mm3 but 1.11 (95% CI 0.78-1.58) at 201-350 cells/mm3. In contrast, the aHR for current CD4 count, comparing >350 with <100 cells/mm3, was 0.10 (95% CI 0.05-0.20).
Conclusions
Absolute CD4 count remains a strong risk for mortality with a stable effect size over the first four years of cART. However, CD4 count slope and HIV RNA provide independently added to the model.
doi:10.1097/QAI.0b013e318287c1fe
PMCID: PMC3655761  PMID: 23344547
8.  Immune recovery after starting ART in HIV-infected patients presenting and not presenting with tuberculosis in South Africa 
We studied the immune response after starting antiretroviral treatment (ART) in 15,646 HIV-infected patients with or without tuberculosis (TB) at presentation in three ART programs in South Africa between 2003–2010. Patients presenting with TB had similar increases in CD4 cells compared to all other patients (adjusted difference 4.9 cells/µl per six months, 95% CI 0.2–9.7). Younger age, advanced clinical stage, female sex, and lower CD4 cell count at ART start were all associated with steeper CD4 slopes. In South Africa HIV-infected patients presenting with TB experience immune recovery after starting ART that is no worse than in other patients.
doi:10.1097/QAI.0b013e318288b39d
PMCID: PMC3671097  PMID: 23364513
tuberculosis; HIV; antiretroviral treatment; immune response; CD4 cell count; linear mixed model
9.  A three-tier framework for monitoring antiretroviral therapy in high HIV burden settings 
The provision of antiretroviral therapy (ART) in low and middle-income countries is a chronic disease intervention of unprecedented magnitude and is the dominant health systems challenge for high-burden countries, many of which rank among the poorest in the world. Substantial external investment, together with the requirement for service evolution to adapt to changing needs, including the constant shift to earlier ART initiation, makes outcome monitoring and reporting particularly important. However, there is growing concern at the inability of many high-burden countries to report on the outcomes of patients who have been in care for various durations, or even the number of patients in care at a particular point in time. In many instances, countries can only report on the number of patients ever started on ART. Despite paper register systems coming under increasing strain, the evolution from paper directly to complex electronic medical record solutions is not viable in many contexts. Implementing a bridging solution, such as a simple offline electronic version of the paper register, can be a pragmatic alternative. This paper describes and recommends a three-tiered monitoring approach in low- and middle-income countries based on the experience implementing such a system in the Western Cape province of South Africa. A three-tier approach allows Ministries of Health to strategically implement one of the tiers in each facility offering ART services. Each tier produces the same nationally required monthly enrolment and quarterly cohort reports so that outputs from the three tiers can be aggregated into a single database at any level of the health system. The choice of tier is based on context and resources at the time of implementation. As resources and infrastructure improve, more facilities will transition to the next highest and more technologically sophisticated tier. Implementing a three-tier monitoring system at country level for pre-antiretroviral wellness, ART, tuberculosis and mother and child health services can be an efficient approach to ensuring system-wide harmonization and accurate monitoring of services, including long term retention in care, during the scale-up of electronic monitoring solutions.
doi:10.7448/IAS.17.1.18908
PMCID: PMC4005043  PMID: 24780511
monitoring; antiretroviral therapy; TIER.Net; HIV; electronic register; three-tier system; eKapa
10.  Tuberculosis and the risk of opportunistic infections and cancers in HIV-infected patients starting ART in Southern Africa 
Objectives
To investigate the incidence of selected opportunistic infections (OIs) and cancers and the role of a history of tuberculosis (TB) as a risk factor for developing these conditions in HIV-infected patients starting antiretroviral treatment (ART) in Southern Africa.
Methods
Five ART programs from Zimbabwe, Zambia and South Africa participated. Outcomes were extrapulmonary cryptococcal disease (CM), pneumonia due to Pneumocystis jirovecii (PCP), Kaposi’s sarcoma and Non-Hodgkin lymphoma. A history of TB was defined as a TB diagnosis before or at the start of ART. We used Cox models adjusted for age, sex, CD4 cell count at ART start and treatment site, presenting results as adjusted hazard ratios (aHR) with 95% confidence intervals (CI).
Results
We analyzed data from 175,212 patients enrolled between 2000–2010 and identified 702 patients with incident CM (including 205 with a TB history) and 487 with incident PCP (including 179 with a TB history). The incidence per 100 person-years over the first year of ART was 0.48 (95% CI 0.44–0.52) for CM, 0.35 (95% CI 0.32–0.38) for PCP, 0.31 (95% CI 0.29–0.35) for Kaposi’s sarcoma and 0.02 (95% CI 0.01–0.03) for Non-Hodgkin lymphoma. A history of TB was associated with cryptococcal disease (aHR 1.28, 95% CI 1.05–1.55) and Pneumocystis jirovecii pneumonia (aHR 1.61, 95% CI 1.27–2.04), but not with Non-Hodgkin lymphoma (aHR 1.09, 95% CI 0.45–2.65) or Kaposi’s sarcoma (aHR 1.02, 95% CI 0.81–1.27).
Conclusions
Our study suggests that there may be interactions between different OIs in HIV-infected patients.
doi:10.1111/tmi.12026
PMCID: PMC3553249  PMID: 23199369
tuberculosis; opportunistic infections; cancer; HIV; risk factors; antiretroviral treatment programs; history of tuberculosis
11.  Effect of Antiretroviral Therapy on the Diagnostic Accuracy of Symptom Screening for Intensified Tuberculosis Case Finding in a South African HIV Clinic 
Diagnostic accuracy of symptom screening to rule out tuberculosis among human immunodeficiency virus–infected individuals undergoing screening prior to isoniazid preventive therapy was evaluated. Symptom screening had poor sensitivity, especially among those on antiretroviral therapy. Without culture-based screening, the risk of inadvertently prescribing isoniazid monotherapy is high.
Background. Current symptom screening algorithms for intensified tuberculosis case finding or prior to isoniazid preventive therapy (IPT) in patients infected with human immunodeficiency virus (HIV) were derived from antiretroviral-naive cohorts. There is a need to validate screening algorithms in patients on antiretroviral therapy (ART).
Methods. We performed cross-sectional evaluation of the diagnostic accuracy of symptom screening, including the World Health Organization (WHO) algorithm, to rule out tuberculosis in HIV-infected individuals pre-ART and on ART undergoing screening prior to IPT.
Results. A total of 1429 participants, 54% on ART, had symptom screening and a sputum culture result available. Culture-positive tuberculosis was diagnosed in 126 patients (8.8%, 95% confidence interval [CI], 7.4%–10.4%). The WHO symptom screen in the on-ART compared with the pre-ART group had a lower sensitivity (23.8% vs 47.6%), but higher specificity (94.4% vs 79.8%). The effect of ART was independent of CD4+ count in multivariable analyses. The posttest probability of tuberculosis following a negative WHO screen was 8.9% (95% CI, 7.4%–10.8%) and 4.4% (95% CI, 3.7%–5.2%) for the pre-ART and on-ART groups, respectively. Addition of body mass index to the WHO screen significantly improved discriminatory ability in both ART groups, which was further improved by adding CD4 count and ART duration.
Conclusions. The WHO symptom screen has poor sensitivity, especially among patients on ART, in a clinic where regular tuberculosis screening is practiced. Consequently, a significant proportion of individuals with tuberculosis would inadvertently be placed on isoniazid monotherapy despite high negative predictive values. Until more sensitive methods of ruling out tuberculosis are established, it would be prudent to do a sputum culture prior to IPT where this is feasible.
doi:10.1093/cid/cis775
PMCID: PMC3501332  PMID: 22955441
12.  Temporal Trends in the Characteristics of Children at Antiretroviral Therapy Initiation in Southern Africa: The IeDEA-SA Collaboration 
PLoS ONE  2013;8(12):e81037.
Background
Since 2005, increasing numbers of children have started antiretroviral therapy (ART) in sub-Saharan Africa and, in recent years, WHO and country treatment guidelines have recommended ART initiation for all infants and very young children, and at higher CD4 thresholds for older children. We examined temporal changes in patient and regimen characteristics at ART start using data from 12 cohorts in 4 countries participating in the IeDEA-SA collaboration.
Methodology/Principal Findings
Data from 30,300 ART-naïve children aged <16 years at ART initiation who started therapy between 2005 and 2010 were analysed. We examined changes in median values for continuous variables using the Cuzick's test for trend over time. We also examined changes in the proportions of patients with particular disease severity characteristics (expressed as a binary variable e.g. WHO Stage III/IV vs I/II) using logistic regression. Between 2005 and 2010 the number of children starting ART each year increased and median age declined from 63 months (2006) to 56 months (2010). Both the proportion of children <1 year and ≥10 years of age increased from 12 to 19% and 18 to 22% respectively. Children had less severe disease at ART initiation in later years with significant declines in the percentage with severe immunosuppression (81 to 63%), WHO Stage III/IV disease (75 to 62%), severe anemia (12 to 7%) and weight-for-age z-score<−3 (31 to 28%). Similar results were seen when restricting to infants with significant declines in the proportion with severe immunodeficiency (98 to 82%) and Stage III/IV disease (81 to 63%). First-line regimen use followed country guidelines.
Conclusions/Significance
Between 2005 and 2010 increasing numbers of children have initiated ART with a decline in disease severity at start of therapy. However, even in 2010, a substantial number of infants and children started ART with advanced disease. These results highlight the importance of efforts to improve access to HIV diagnostic testing and ART in children.
doi:10.1371/journal.pone.0081037
PMCID: PMC3867284  PMID: 24363808
13.  The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure 
Tropical medicine & international health : TM & IH  2012;17(11):10.1111/j.1365-3156.2012.03073.x.
Objectives
To determine the improvement in positive predictive value of immunological failure criteria for identifying virological failure in HIV-infected children on antiretroviral therapy (ART) when a single targeted viral load measurement is performed in children identified as having immunological failure.
Methods
Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/percent and HIV-RNA monitoring are performed 6-monthly. Immunological failure was defined according to both WHO 2010 and United States DHHS 2008 criteria. Confirmed virological failure was defined as HIV-RNA >5000 copies/ml on 2 consecutive occasions <365 days apart in a child on ART for ≥18 months.
Results
Among 2798 children on ART for ≥18 months (median [IQR] age: 50 (21–84) months at ART initiation), the cumulative probability of confirmed virological failure by 42 months on ART was 6.3%. Using targeted viral load after meeting DHHS immunological failure criteria rather than DHHS IF criteria alone increased PPV from 28% to 82%. Targeted viral load improved the positive predictive value of WHO 2010 criteria for identifying confirmed virological failure from 49% to 82%.
Conclusion
The addition of a single viral load measurement in children identified as failing immunologically will prevent most switches to second-line treatment in virologically suppressed children.
doi:10.1111/j.1365-3156.2012.03073.x
PMCID: PMC3830726  PMID: 22974345
HIV virological failure children; antiretroviral therapy; monitoring immunological failure
15.  Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy - The IeDEA Southern Africa Collaboration 
Summary
Objectives
To determine the diagnostic accuracy of World Health Organization (WHO) 2010 and 2006 as well as United States Department of Health and Human Services (DHHS) 2008 definitions of immunological failure for identifying virological failure in children on antiretroviral therapy (ART).
Methods
Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/percent and HIV-RNA monitoring are performed 6-monthly. Incomplete virological suppression (IVS) was defined as failure to achieve ≥1 HIV-RNA ≤400 copies/mL between 6 and 15 months on ART and viral rebound (VR) as confirmed HIV-RNA ≥5000 copies/mL in a child on ART for ≥18 months who had achieved suppression during the first year on treatment.
Results
Among 3115 children (median (IQR) age 48 (20-84) months at ART initiation) on treatment for ≥1 year, sensitivity of immunological criteria for IVS was 10%, 6% and 26% for WHO 2006 2010 and DHHS 2008 criteria respectively. The corresponding positive predictive values (PPV) were 31% 20% and 20%. Diagnostic accuracy for VR was determined in 2513 children with ≥18 months of follow-up and virological suppression during the first year on ART with sensitivity of 5% (WHO 2006/2010) and 27% (DHHS 2008). PPV results were 42% (WHO 2010), 43% (WHO 2006) and 20% (DHHS 2008).
Conclusion
Current immunological criteria are unable to correctly identify children failing ART virologically. Improved access to viral load testing is needed to reliably identify virological failure in children.
doi:10.1111/j.1365-3156.2011.02854.x
PMCID: PMC3783841  PMID: 21834797
children; antiretroviral therapy; immunological criteria; sensitivity, specificity; virological failure
16.  The Causal Effect of Switching to Second–line ART in Programmes without Access to Routine Viral Load Monitoring 
AIDS (London, England)  2012;26(1):57-65.
Objectives
We examined the effect of switching to second-line antiretroviral therapy (ART) on mortality in patients who experienced immunological failure in ART programmes without access to routine viral load monitoring in sub-Saharan Africa.
Design and setting
Collaborative analysis of two ART programmes in Lusaka, Zambia and Lilongwe, Malawi.
Methods
We included all adult patients experiencing immunological failure based on WHO criteria. We used Cox proportional hazards models weighted by the inverse probability of switching to compare mortality between patients who switched and patients who did not; and between patients who switched immediately and patients who switched later. Results are expressed as hazard ratios (HR) with 95% credible intervals (95% CI).
Results
Among 2,411 patients with immunological failure 324 patients (13.4%) switched to second-line ART during 3932person-years of follow-up. The median CD4 cell count at start of ART and failure was lower in patients who switched compared to patients who did not: 80 versus 155 cells/μL (p<0.001) and 77 versus 146 cells/μL (p<0.001), respectively.Adjusting for baseline and time-dependent confounders, mortality was lower among patients who switched compared to patients remaining on failing first-line ART: HR0.25 (95%CI 0.09-0.72). Mortality was also lower among patients who remained on failing first-line ART for shorter periods: HR 0.70 (95% CI 0.44-1.09) per 6 months shorter exposure.
Conclusion
In ART programmes switching patients to second-line regimens based on WHO immunological failure criteria appears to reduce mortality, with the greatest benefit in patients switching immediately after immunological failure is diagnosed.
doi:10.1097/QAD.0b013e32834e1b5f
PMCID: PMC3759359  PMID: 22089376
17.  Tenofovir in second-line ART in Zambia and South Africa: Collaborative analysis of cohort studies 
Objectives
Tenofovir (TDF) is increasingly used in second-line antiretroviral treatment (ART) in sub-Saharan Africa. We compared outcomes of second-line ART containing and not containing TDF in cohort studies from Zambia and the Republic of South Africa (RSA).
Methods
Patients aged ≥ 16 years starting protease inhibitor-based second-line ART in Zambia (1 cohort) and RSA (5 cohorts) were included. We compared mortality, immunological failure (all cohorts) and virological failure (RSA only) between patients receiving and not receiving TDF. Competing risk models and Cox models adjusted for age, sex, CD4 count, time on first-line ART and calendar year were used to analyse mortality and treatment failure, respectively. Hazard ratios (HRs) were combined in fixed-effects meta-analysis.
Findings
1,687 patients from Zambia and 1,556 patients from RSA, including 1,350 (80.0%) and 206 (13.2%) patients starting TDF, were followed over 4,471 person-years. Patients on TDF were more likely to have started second-line ART in recent years, and had slightly higher baseline CD4 counts than patients not on TDF. Overall 127 patients died, 532 were lost to follow-up and 240 patients developed immunological failure. In RSA 94 patients had virologic failure. Combined HRs comparing tenofovir with other regimens were 0.60 (95% CI 0.41–0.87) for immunologic failure and 0.63 (0.38–1.05) for mortality. The HR for virologic failure in RSA was 0.28 (0.09–0.90).
Conclusions
In this observational study patients on TDF-containing second-line ART were less likely to develop treatment failure than patients on other regimens. TDF seems to be an effective component of second-line ART in southern Africa.
doi:10.1097/QAI.0b013e3182632540
PMCID: PMC3432418  PMID: 22743595
Tenofovir; second-line antiretroviral therapy; southern Africa; treatment failure; mortality
18.  Viral load monitoring of antiretroviral therapy, cohort viral load and HIV transmission in Southern Africa: A mathematical modelling analysis 
AIDS (London, England)  2012;26(11):1403-1413.
Objectives
In low-income settings treatment failure is often identified using CD4 cell count monitoring. Consequently, patients remain on a failing regimen, resulting in a higher risk of transmission. We investigated the benefit of routine viral load monitoring for reducing HIV transmission.
Design
Mathematical model
Methods
We developed a stochastic mathematical model representing the course of individual viral load, immunological response and survival in a cohort of 1,000 HIV infected patients receiving antiretroviral therapy (ART) in southern Africa. We calculated cohort viral load (sum of individual viral loads) and used a mathematical relationship between individual viral load values and transmission probability to estimate the number of new HIV infections. Our model was parameterized with data from the IeDEA Southern African collaboration. Sensitivity analyses were performed to assess the validity of the results in a universal ‘test and treat’ scenario where patients start ART earlier after HIV infection.
Results
If CD4 cell count alone was regularly monitored, the cohort viral load was 2.6*106 copies/mL and the treated patients transmitted on average 6.3 infections each year. With routine viral load monitoring, both cohort viral load and transmissions were reduced by 31% to 1.7*106 copies/mL and 4.3 transmissions, respectively. The relative reduction of 31% between monitoring strategies remained similar for different scenarios.
Conclusions
While routine viral load monitoring enhances the preventive effect of ART, the provision of ART to everyone in need should remain the highest priority.
doi:10.1097/QAD.0b013e3283536988
PMCID: PMC3750130  PMID: 22421243
mathematical model; Southern Africa; HIV transmission; viral load monitoring; therapy failure; second-line therapy; test and treat
19.  Rates and Predictors of Failure of First-line Antiretroviral Therapy and Switch to Second-line ART in South Africa 
Objectives
To measure rates and predictors of virologic failure and switch to second-line ART in South Africa.
Design
Observational cohort study
Methods
We included ART-naïve adult patients initiated on public-sector ART (Jan 2000–July 2008) at five sites in South Africa who completed ≥6 months of follow-up. We estimated cumulative risk of virologic failure (viral load ≥400 copies/ml with confirmation above varying thresholds) and switching to second-line ART.
Results
19,645 patients (29,935 person-years) had a median of 1.3 years of study follow-up (1.8 years on ART) and a median CD4 count of 96 (IQR:40–159) cells/μl at ART initiation. 9.9% (4.5/100 person-years) failed ART in median 16 (IQR:12–23) months since ART initiation, with median 2.9 (IQR:1.8–5.0) months between first elevated and confirmatory viral loads. By survival analysis, using a confirmatory threshold of 400 copies/ml, 16.9% (95%CI:15.4–18.6%) failed by five years on ART, but only 7.8% (95%CI:6.6%-9.3%) using a threshold of 10,000. CD4 <25 vs. 100–199 (adjusted HR:1.57;95%CI 1.35–1.83), ART initiation viral load ≥1,000,000 vs. <10,000, (1.32;0.91–1.93) and 2+ gaps in care vs. 0 (95%CI:6.61; 4.52–9.68) were predictive of failure. Overall 10.1% (95%CI:9.0%-11.4%) switched to second-line by five years on ART. Lower CD4 at failure and higher rate of CD4 decline were predictive of switch (decline 100% to 51% vs. 25% to −25%, adjusted HR:1.96;95%CI:1.35–2.85).
Conclusions
In resource-limited settings with viral load monitoring, virologic failure rates are highly sensitive to thresholds for confirmation. Despite clear guidelines there is considerable variability in switching failing patients, partially in response to immunologic status and post-failure evolution.
doi:10.1097/QAI.0b013e3182557785
PMCID: PMC3392418  PMID: 22433846
HIV; AIDS; antiretroviral therapy; viral load; virologic treatment failure; second line
20.  Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy 
Summary
OBJECTIVES
To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment.
METHODS
Analysis of 10 treatment programmes in Africa and South America that monitor both CD4 cell counts and HIV-1 viral load. Adult patients with at least two CD4 counts and viral load measurements between month 6 and 18 after starting a non-nucleoside reverse transcriptase inhibitor-based regimen were included. WHO immunological criteria include CD4 counts persistently <100 cells/μl, a fall below the baseline CD4 count, or a fall of >50% from the peak value. Virological failure was defined as two measurements ≥10 0000 copies/ml (higher threshold) or ≥500 copies/ml (lower threshold). Measures of accuracy with exact binomial 95% confidence intervals (CI) were calculated.
RESULTS
A total of 2009 patients were included. During 1856 person-years of follow up 63 patients met the immunological criteria and 35 patients (higher threshold) and 95 patients (lower threshold) met the virological criteria. Sensitivity [95% confidence interval (CI)] was 17.1% (6.6–33.6%) for the higher and 12.6% (6.7–21.0%) for the lower threshold. Corresponding results for specificity were 97.1% (96.3–97.8%) and 97.3% (96.5–98.0%), for positive predictive value 9.5% (3.6–19.6%) and 19.0% (10.2–30.9%) and for negative predictive value 98.5% (97.9–99.0%) and 95.7% (94.7–96.6%).
CONCLUSIONS
The positive predictive value of the WHO immunological criteria for virological failure of antiretroviral treatment in resource-limited settings is poor, but the negative predictive value is high. Immunological criteria are more appropriate for ruling out than for ruling in virological failure in resource-limited settings.
doi:10.1111/j.1365-3156.2009.02338.x
PMCID: PMC3722497  PMID: 19624478
highly active antiretroviral therapy; treatment failure; CD4 lymphocyte count; viral load; diagnostic techniques and procedures; Africa
21.  Time to Initiation of Antiretroviral Therapy Among Patients With HIV-Associated Tuberculosis in Cape Town, South Africa 
We studied the time interval between starting tuberculosis treatment and commencing antiretroviral treatment (ART) in HIV-infected patients (n=1433; median CD4 count 71 cells/μL, IQR,32-132) attending three South African township ART services between 2002-2008. The overall median delay was 2.66 months (IQR,1.58-4.17). In adjusted analyses, delays varied between treatment sites but were shorter for patients with lower CD4 counts and those treated in more recent calendar years. During the most recent period (2007-2008), 4.7%, 19.7% and 51.1% of patients started ART within 2, 4 and 8 weeks of TB treatment, respectively. Operational barriers must be tackled to permit further acceleration of ART initiation as recommended by 2010 WHO ART guidelines.
doi:10.1097/QAI.0b013e3182199ee9
PMCID: PMC3717455  PMID: 21436714
tuberculosis; antiretroviral; timing; delay; Africa
22.  Treatment Response and Mortality among Patients Starting Antiretroviral Therapy with and without Kaposi Sarcoma: A Cohort Study 
PLoS ONE  2013;8(6):e64392.
Background
Improved survival among HIV-infected individuals on antiretroviral therapy (ART) has focused attention on AIDS-related cancers including Kaposi sarcoma (KS). However, the effect of KS on response to ART is not well-described in Southern Africa. We assessed the effect of KS on survival and immunologic and virologic treatment responses at 6- and 12-months after initiation of ART.
Methods
We analyzed prospectively collected data from a cohort of HIV-infected adults initiating ART in South Africa. Differences in mortality between those with and without KS at ART initiation were estimated with Cox proportional hazard models. Log-binomial models were used to assess differences in CD4 count response and HIV virologic suppression within a year of initiating treatment.
Results
Between January 2001–January 2008, 13,847 HIV-infected adults initiated ART at the study clinics. Those with KS at ART initiation (n = 247, 2%) were similar to those without KS (n = 13600,98%) with respect to age (35 vs. 35yrs), presenting CD4 count (74 vs. 85cells/mm3) and proportion on TB treatment (37% vs. 30%). In models adjusted for sex, baseline CD4 count, age, treatment site, tuberculosis and year of ART initiation, KS patients were over three times more likely to have died at any time after ART initiation (hazard ratio[HR]: 3.62; 95% CI: 2.71–4.84) than those without KS. The increased risk was highest within the first year on ART (HR: 4.05; 95% CI: 2.95–5.55) and attenuated thereafter (HR: 2.30; 95% CI: 1.08–4.89). Those with KS also gained, on average, 29 fewer CD4 cells (95% CI: 7–52cells/mm3) and were less likely to increase their CD4 count by 50 cells from baseline (RR: 1.43; 95% CI: 0.99–2.06) within the first 6-months of treatment.
Conclusions
HIV-infected adults presenting with KS have increased risk of mortality even after initiation of ART with the greatest risk in the first year. Among those who survive the first year on therapy, subjects with KS demonstrated a poorer immunologic response to ART than those without KS.
doi:10.1371/journal.pone.0064392
PMCID: PMC3673971  PMID: 23755122
23.  Life Expectancies of South African Adults Starting Antiretroviral Treatment: Collaborative Analysis of Cohort Studies 
PLoS Medicine  2013;10(4):e1001418.
Leigh Johnson and colleagues estimate the life expectancies of HIV positive South African adults who are taking antiretroviral therapy by using information from 6 programmes between 2001 and 2010.
Background
Few estimates exist of the life expectancy of HIV-positive adults receiving antiretroviral treatment (ART) in low- and middle-income countries. We aimed to estimate the life expectancy of patients starting ART in South Africa and compare it with that of HIV-negative adults.
Methods and Findings
Data were collected from six South African ART cohorts. Analysis was restricted to 37,740 HIV-positive adults starting ART for the first time. Estimates of mortality were obtained by linking patient records to the national population register. Relative survival models were used to estimate the excess mortality attributable to HIV by age, for different baseline CD4 categories and different durations. Non-HIV mortality was estimated using a South African demographic model. The average life expectancy of men starting ART varied between 27.6 y (95% CI: 25.2–30.2) at age 20 y and 10.1 y (95% CI: 9.3–10.8) at age 60 y, while estimates for women at the same ages were substantially higher, at 36.8 y (95% CI: 34.0–39.7) and 14.4 y (95% CI: 13.3–15.3), respectively. The life expectancy of a 20-y-old woman was 43.1 y (95% CI: 40.1–46.0) if her baseline CD4 count was ≥200 cells/µl, compared to 29.5 y (95% CI: 26.2–33.0) if her baseline CD4 count was <50 cells/µl. Life expectancies of patients with baseline CD4 counts ≥200 cells/µl were between 70% and 86% of those in HIV-negative adults of the same age and sex, and life expectancies were increased by 15%–20% in patients who had survived 2 y after starting ART. However, the analysis was limited by a lack of mortality data at longer durations.
Conclusions
South African HIV-positive adults can have a near-normal life expectancy, provided that they start ART before their CD4 count drops below 200 cells/µl. These findings demonstrate that the near-normal life expectancies of HIV-positive individuals receiving ART in high-income countries can apply to low- and middle-income countries as well.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
According to the latest figures, more than 34 million people worldwide currently live with HIV/AIDS. In 2011, an estimated 2.5 million people were newly infected with HIV, and in the same year 1.7 million people died from AIDS. Since the beginning of the epidemic in the 1980s, more than 60 million people have contracted HIV and nearly 30 million have died of HIV-related causes. Despite the stark statistics, the life expectancy for people infected with the AIDS virus has dramatically improved over the past decade since the introduction of an effective combination of antiretroviral drugs. In high-income countries, people who are HIV-positive can expect a near-normal life expectancy if they take these drugs (as antiretroviral treatment—ART) throughout their life.
Why Was This Study Done?
Recent studies investigating the life expectancy of people living with HIV have mostly focused on the situation in high-income settings. The situation in low- and middle-income countries is vastly different. People who are diagnosed with HIV are often late in starting treatment, treatments regimes are sometimes interrupted, and a large proportion of patients are lost to follow-up. It is important to gain a realistic estimate of life expectancy in low- and middle-income countries so patients can be given the best information. So in this study the researchers used a model to estimate the life expectancy of patients starting ART in South Africa, using data from several ART programs.
What Did the Researchers Do and Find?
The researchers used data collected from six programs in South Africa based in Western Cape, Gauteng, and KwaZulu-Natal between 2001 and 2010. The researchers calculated the observation time from the time of ART initiation to the date of death or to the end of the study. Then the researchers used a relative survival approach to model the excess mortality attributable to HIV, relative to non-HIV mortality rates in South Africa, over different periods from ART initiation.
Using these methods, the researchers found that over the time period, 37,740 adults started ART and 2,066 deaths were recorded in patient record systems. Of the 16,250 patients who were lost to follow-up, the researchers identified 2,947 further deaths in the population register. When they inputted these figures into their model, the researchers estimated that the mortality rate was 83.2 per 1,000 person-years of observation (PYO), and was higher in males (99.8 per 1,000 PYO) than in females (72.6 per 1,000 PYO). The researchers also found that the most significant factor determining the life expectancy of treated patients was their age at ART initiation: the average life expectancy of men starting ART varied between 27.6 years at age 20 and 10.1 years at age 60, while corresponding estimates in women were 36.8 and 14.4, respectively. Life expectancies were also significantly influenced by baseline CD4 counts; life expectancies in patients with baseline CD4 counts ≥200 cells/µl were between 70% and 86% of those of HIV-negative adults of the same age and sex, while patients starting ART with CD4 counts of <50 cells/µl had life expectancies that were between 48% and 61% of those of HIV-negative adults. Importantly, the researchers found that life expectancies were also 15%–20% higher in patients who survived their first 24 months after starting ART than in patients of the same age who had just started therapy.
What Do These Findings Mean?
These findings suggest that in South Africa, patients starting ART have life expectancies around 80% of normal life expectancy, provided that they start treatment before their CD4 count drops below 200 cells/µl. Although these results are encouraging, this study highlights that health services must overcome major challenges, such as dealing with late diagnosis, low uptake of CD4 testing, loss from pre-ART care, and delayed ART initiation, if near-normal life expectancies are to be achieved for the majority of HIV-positive South Africans. With the anticipated increase in the fraction of patients starting ART at higher CD4 counts in the future, long-term survival can be expected to increase even further. It is therefore critical that appropriate funding systems and innovative ways to reduce costs are put in place, to ensure the long-term sustainability of ART delivery in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001418.
The International Epidemiologic Databases to Evaluate AIDS has more statistical information from world regions
amfAR, the Foundation for AIDS Research, works with health care workers and AIDS organizations in developing countries to create and implement effective HIV research, treatment, prevention, and education strategies
doi:10.1371/journal.pmed.1001418
PMCID: PMC3621664  PMID: 23585736
24.  Outcomes of Antiretroviral Treatment in Programmes with and without Routine Viral Load Monitoring in Southern Africa 
AIDS (London, England)  2011;25(14):1761-1769.
Objectives
To compare outcomes of antiretroviral therapy (ART) in South Africa, where viral load monitoring is routine, with Malawi and Zambia, where monitoring is based on CD4 cell counts.
Methods
We included 18,706 adult patients starting ART in South Africa and 80,937 patients starting in Zambia or Malawi. We examined CD4 responses in models for repeated measures, and the probability of switching to second-line regimens, mortality and loss to follow-up in multi-state models, measuring time from six months.
Findings
In South Africa 9.8% (9.1–10.5%) had switched at 3 years, 1.3% (95% CI 0.9–1.6%) remained on failing first-line regimens, 9.2% (8.5–9.8%) were lost to follow-up and 4.3% (3.9–4.8%) had died. In Malawi and Zambia more patients were on a failing first-line regimen (3.7%, 3.6–3.9%), fewer patients had switched (2.1%, 2.0–2.3%) and more patients were lost (15.3%, 15.0–15.6%) or had died (6.3%, 6.0–6.5%). Median CD4 cell counts were lower in South Africa at start of ART (93 vs. 132 cells/µL, p<0.001) but higher after 3 years (425 vs. 383 cells/µL, p<0.001). The hazard ratio comparing South Africa with Malawi and Zambia, adjusted for age, sex, first-line regimen and CD4 cell count, was 0.58 (95% CI 0.50–0.66) for death and 0.53 (0.48–0.58) for loss to follow-up.
Conclusions
Over 3 years of ART mortality was lower in South Africa than in Malawi or Zambia. The more favourable outcome in South Africa might be explained by viral load monitoring leading to earlier detection of treatment failure, adherence counselling and timelier switching to second-line ART.
doi:10.1097/QAD.0b013e328349822f
PMCID: PMC3605707  PMID: 21681057
25.  Monitoring of Antiretroviral Therapy and Mortality in HIV Programmes in Malawi, South Africa and Zambia: Mathematical Modelling Study 
PLoS ONE  2013;8(2):e57611.
Objectives
Mortality in patients starting antiretroviral therapy (ART) is higher in Malawi and Zambia than in South Africa. We examined whether different monitoring of ART (viral load [VL] in South Africa and CD4 count in Malawi and Zambia) could explain this mortality difference.
Design:
Mathematical modelling study based on data from ART programmes.
Methods
We used a stochastic simulation model to study the effect of VL monitoring on mortality over 5 years. In baseline scenario A all parameters were identical between strategies except for more timely and complete detection of treatment failure with VL monitoring. Additional scenarios introduced delays in switching to second-line ART (scenario B) or higher virologic failure rates (due to worse adherence) when monitoring was based on CD4 counts only (scenario C). Results are presented as relative risks (RR) with 95% prediction intervals and percent of observed mortality difference explained.
Results
RRs comparing VL with CD4 cell count monitoring were 0.94 (0.74–1.03) in scenario A, 0.94 (0.77–1.02) with delayed switching (scenario B) and 0.80 (0.44–1.07) when assuming a 3-times higher rate of failure (scenario C). The observed mortality at 3 years was 10.9% in Malawi and Zambia and 8.6% in South Africa (absolute difference 2.3%). The percentage of the mortality difference explained by VL monitoring ranged from 4% (scenario A) to 32% (scenarios B and C combined, assuming a 3-times higher failure rate). Eleven percent was explained by non-HIV related mortality.
Conclusions
VL monitoring reduces mortality moderately when assuming improved adherence and decreased failure rates.
doi:10.1371/journal.pone.0057611
PMCID: PMC3585414  PMID: 23469035

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