Sustained Virological Response on Second-Line Antiretroviral Therapy following Virological Failure in HIV-Infected Patients in Rural South Africa

Objective

This study aims to describe the virological, immunological and clinical efficacy of protease inhibitor (PI)-based second-line antiretroviral therapy (ART) in rural South Africa.

Methods

An observational cohort study was performed on 210 patients (including 39 children) who initiated PI-based second-line therapy at least 12 months prior to data collection. Biannual clinical, immunological and virological monitoring was performed. Primary endpoints were adequate virological response (plasma HIV-1 RNA<400 copies/ml), full virological suppression (plasma HIV-1 RNA<50 copies/ml) and treatment failure (virological failure (plasma HIV-1 RNA>1000 after initial virological response) or on-going viremia (plasma HIV-1 RNA never<400 copies/ml for more than six months)). Data were analyzed by an on-treatment (OT) and intention-to-treat (ITT) approach. Analyses were primarily performed on the group of patients who switched following first-line virological failure.

Results

Median duration of follow-up after switch to second-line treatment was 20 months [IQR 11–35]. 191 patients had switched to second-line ART due to first-line virological failure. 139/191 of them (72.8%, ITT) were in care and on treatment at the end of follow-up and 11/191 (5.8%, ITT) had died. After twelve months, an adequate virological response was seen in 92/128 patients (71.9%, OT), of which 78/128 (60.9%, OT) experienced full virological suppression. Virological response remained stable after 24 months. Virological efficacy was similar amongst adult and pediatric patients. As in first-line ART, we observed a lack of correlation between virological failure and WHO-defined immunological failure.

Conclusions

Good virological outcomes following first-line failure can be achieved with PI-based, second-line antiretroviral therapy in both adult and pediatric patients in rural South Africa. Retention rates were high and virological outcomes were sustainable during the two-year follow-up period, although persisting low-level viremia occurred in a subset of patients. The observed viro-immunological dissociation emphasizes the need for virological monitoring.     

Virological Response and Antiretroviral Drug Resistance Emerging during Antiretroviral Therapy at Three Treatment Centers in Uganda

Background

With the scale-up of antiretroviral therapy (ART), monitoring programme performance is needed to maximize ART efficacy and limit HIV drug resistance (HIVDR).

Methods

We implemented a WHO HIVDR prospective survey protocol at three treatment centers between 2012 and 2013. Data were abstracted from patient records at ART start (T1) and after 12 months (T2). Genotyping was performed in the HIV pol region at the two time points.

Results

Of the 425 patients enrolled, at T2, 20 (4.7%) had died, 66 (15.5%) were lost to follow-up, 313 (73.6%) were still on first-line, 8 (1.9%) had switched to second-line, 17 (4.0%) had transferred out and 1 (0.2%) had stopped treatment. At T2, 272 out of 321 on first and second line (84.7%) suppressed below 1000 copies/ml and the HIV DR prevention rate was 70.1%, just within the WHO threshold of ≥70%. The proportion of participants with potential HIVDR was 20.9%, which is higher than the 18.8% based on pooled analyses from African studies. Of the 35 patients with mutations at T2, 80% had M184V/I, 65.7% Y181C, and 48.6% (54.8% excluding those not on Tenofovir) had K65R mutations. 22.9% had Thymidine Analogue Mutations (TAMs). Factors significantly associated with HIVDR prevention at T2 were: baseline viral load (VL) <100,000 copies/ml [Adjusted odds ratio (AOR) 3.13, 95% confidence interval (CI): 1.36–7.19] and facility. Independent baseline predictors for HIVDR mutations at T2 were: CD4 count <250 cells/μl (AOR 2.80, 95% CI: 1.08–7.29) and viral load ≥100,000 copies/ml (AOR 2.48, 95% CI: 1.00–6.14).

Conclusion

Strengthening defaulter tracing, intensified follow-up for patients with low CD4 counts and/or high VL at ART initiation together with early treatment initiation above 250 CD4 cells/ul and adequate patient counselling would improve ART efficacy and HIVDR prevention. The high rate of K65R and TAMs could compromise second line regimens including NRTIs.     

Causes of Death on Antiretroviral Therapy: A Post-Mortem Study from South Africa

Background

Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients.

Methods

HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death.

Results

Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7–90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death.

Conclusions

Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.     

Implementation of an Electronic Monitoring and Evaluation System for the Antiretroviral Treatment Programme in the Cape Winelands District,South Africa: A Qualitative Evaluation

BackgroundA pragmatic three-tiered approach to monitor the world’s largest antiretroviral treatment (ART) programme was adopted by the South African National Department of Health in 2010. With the rapid expansion of the programme, the limitations of the paper-based register (tier 1) were the catalyst for implementation of the stand-alone electronic register (tier 2), which offers simple digitisation of the paper-based register. This article engages with theory on implementation to identify and contextualise enabling and constraining factors for implementation of the electronic register, to describe experiences and use of the register, and to make recommendations for implementation in similar settings where standardisation of ART monitoring and evaluation has not been achieved.MethodsWe conducted a qualitative evaluation of the roll-out of the register. This comprised twenty in-depth interviews with a diverse sample of stakeholders at facility, sub-district, and district levels of the health system. Facility-level participants were selected across five sub-districts, including one facility per sub-district. Responses were coded and analysed using a thematic approach. An implementation science framework guided interpretation of the data.ConclusionIn this study we found that relative advantage of an intervention and stakeholder engagement are critical to implementation. We suggest that without these aspects of implementation, formative and summative outcomes of implementation at both the adoption and coalface stages of implementation would be negatively affected.     

Impact of Previous Virological Treatment Failures and Adherence on the Outcome of Antiretroviral Therapy in 2007

Background

Combination antiretroviral treatment (cART) has been very successful, especially among selected patients in clinical trials. The aim of this study was to describe outcomes of cART on the population level in a large national cohort.

Methods

Characteristics of participants of the Swiss HIV Cohort Study on stable cART at two semiannual visits in 2007 were analyzed with respect to era of treatment initiation, number of previous virologically failed regimens and self reported adherence. Starting ART in the mono/dual era before HIV-1 RNA assays became available was counted as one failed regimen. Logistic regression was used to identify risk factors for virological failure between the two consecutive visits.

Results

Of 4541 patients 31.2% and 68.8% had initiated therapy in the mono/dual and cART era, respectively, and been on treatment for a median of 11.7 vs. 5.7 years. At visit 1 in 2007, the mean number of previous failed regimens was 3.2 vs. 0.5 and the viral load was undetectable (<50 copies/ml) in 84.6% vs. 89.1% of the participants, respectively. Adjusted odds ratios of a detectable viral load at visit 2 for participants from the mono/dual era with a history of 2 and 3, 4, >4 previous failures compared to 1 were 0.9 (95% CI 0.4–1.7), 0.8 (0.4–1.6), 1.6 (0.8–3.2), 3.3 (1.7–6.6) respectively, and 2.3 (1.1–4.8) for >2 missed cART doses during the last month, compared to perfect adherence. From the cART era, odds ratios with a history of 1, 2 and >2 previous failures compared to none were 1.8 (95% CI 1.3–2.5), 2.8 (1.7–4.5) and 7.8 (4.5–13.5), respectively, and 2.8 (1.6–4.8) for >2 missed cART doses during the last month, compared to perfect adherence.

Conclusions

A higher number of previous virologically failed regimens, and imperfect adherence to therapy were independent predictors of imminent virological failure.     

Loss from Treatment for Drug Resistant Tuberculosis: Risk Factors and Patient Outcomes in a Community-Based Program in Khayelitsha,South Africa

Background

A community based drug resistant tuberculosis (DR-TB) program has been incrementally implemented in Khayelitsha, a high HIV and TB burden community in South Africa. We investigated loss from treatment (LFT), and post treatment outcomes of DR-TB patients in this setting.

Methodology

LFT, defined as interruption of treatment for ≥2 consecutive months was assessed among patients initiating DR-TB treatment for the first time between January 2009 and July 2011. Patients were traced through routine data sources to identify those who subsequently restarted treatment and those who died. Additional information on patient status and survival after LTF was obtained from community DR-TB counselors and from the national death registry. Post treatment outcomes were observed until July 2013.

Results

Among 452 patients initiating treatment for the first time within the given period, 30% (136) were LFT, with 67% retention at 18 months. Treatment was restarted in 27 (20%) patients, with additional resistance recorded in 2/25 (8%), excluding two with presumed DR-TB. Overall, 34 (25%) patients died, including 11 who restarted treatment. Males and those in the age category 15-25 years had a greater hazard of LFT; HR 1.93 (95% CI 1.35-2.75), and 2.43 (95% CI 1.52-3.88) respectively. Older age (>35 years) was associated with a greater hazard of death; HR 3.74 (1.13- 12.37) post treatment. Overall two-year survival was 62%. It was lower (45%) in older patients, and was 92% among those who received >12 months treatment.

Conclusion

LFT was high, occurred throughout the treatment period and was particularly high among males and those aged 15-25 years. Overall long term survival was poor. High rates of LFT should however not preclude scale up of community based care given its impact in increasing access to treatment. Further research is needed to support retention of DR-TB patients on treatment, even within community based treatment programs.     

The Pattern of Attrition from an Antiretroviral Treatment Program in Nigeria

Objective

To evaluate the rate and factors associated with attrition of patients receiving ART in tertiary and secondary hospitals in Nigeria.

Methods and Findings

We reviewed patient level data collected between 2007 and 2010 from 11 hospitals across Nigeria. Kaplan-Meier product-limit and Cox regression were used to determine probability of retention in care and risk factors for attrition respectively. Of 6,408 patients in the cohort, 3,839 (59.9%) were females, median age of study population was 33years (IQR: 27–40) and 4,415 (69%) were from secondary health facilities. The NRTI backbone was Stavudine (D4T) in 3708 (57.9%) and Zidovudine (ZDV) in 2613 (40.8%) of patients. Patients lost to follow up accounted for 62.7% of all attrition followed by treatment stops (25.3%) and deaths (12.0%). Attrition was 14.1 (N = 624) and 15.1% (N = 300) in secondary and tertiary hospitals respectively (p = 0.169) in the first 12 months on follow up. During the 13 to 24 months follow up period, attrition was 10.7% (N = 407) and 19.6% (N = 332) in secondary and tertiary facilities respectively (p<0.001). Median time to lost to follow up was 11.1 (IQR: 6.1 to 18.5) months in secondary compared with 13.6 (IQR: 9.9 to 17.0) months in tertiary sites (p = 0.002). At 24 months follow up, male gender [AHR 1.18, 95% CI: 1.01–1.37, P = 0.038]; WHO clinical stage III [AHR 1.30, 95%CI: 1.03–1.66, P = 0.03] and clinical stage IV [AHR 1.90, 95%CI: 1.20–3.02, p = 0.007] and care in a tertiary hospital [AHR 2.21, 95% CI: 1.83–2.67, p<0.001], were associated with attrition.

Conclusion

Attrition could potentially be reduced by decentralizing patients on ART after the first 12 months on therapy to lower level facilities, earlier initiation on treatment and strengthening adherence counseling amongst males.     

Population-Based CD4 Counts in a Rural Area in South Africa with High HIV Prevalence and High Antiretroviral Treatment Coverage

Background

Little is known about the variability of CD4 counts in the general population of sub-Saharan Africa countries affected by the HIV epidemic. We investigated factors associated with CD4 counts in a rural area in South Africa with high HIV prevalence and high antiretroviral treatment (ART) coverage.

Methods

CD4 counts, health status, body mass index (BMI), demographic characteristics and HIV status were assessed in 4990 adult resident participants of a demographic surveillance in rural KwaZulu-Natal in South Africa; antiretroviral treatment duration was obtained from a linked clinical database. Multivariable regression analysis, overall and stratified by HIV status, was performed with CD4 count levels as outcome.

Results

Median CD4 counts were significantly higher in women than in men overall (714 vs. 630 cells/µl, p<0.0001), both in HIV-uninfected (833 vs. 683 cells/µl, p<0.0001) and HIV-infected adults (384.5 vs. 333 cells/µl, p<0.0001). In multivariable regression analysis, women had 19.4% (95% confidence interval (CI) 16.1–22.9) higher CD4 counts than men, controlling for age, HIV status, urban/rural residence, household wealth, education, BMI, self-reported tuberculosis, high blood pressure, other chronic illnesses and sample processing delay. At ART initiation, HIV-infected adults had 21.7% (95% CI 14.6–28.2) lower CD4 counts than treatment-naive individuals; CD4 counts were estimated to increase by 9.2% (95% CI 6.2–12.4) per year of treatment.

Conclusions

CD4 counts are primarily determined by sex in HIV-uninfected adults, and by sex, age and duration of antiretroviral treatment in HIV-infected adults. Lower CD4 counts at ART initiation in men could be a consequence of lower CD4 cell counts before HIV acquisition.     

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

Objective

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

Design

Cross-sectional cohort study.

Methods

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

Results

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

Conclusions

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

HIV Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential Impact of Antiretroviral Therapy on HIV Incidence in South Africa

Background

Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART.

Methods and Findings

Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results.

Conclusions

Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact. Please see later in the article for the Editors'' Summary     

The Virological and Immunological Characteristics of the HIV-1-Infected Population in Brazil: From Initial Diagnosis to Impact of Antiretroviral Use

BackgroundImmunological and virological status of HIV-infected individuals entering the Brazilian public system over time was analyzed. We evaluated the impact of ART on virological, immunological and antiretroviral resistance over time.MethodsCD4+ T cell counts, viral loads and genotypes from patients over 13 years old from 2001–2011 were analyzed according to demographic data. We compared groups using parametric t-tests and linear regression analysis in the R statistical software language.ResultsMean baseline CD4+ T cell counts varied from 348 (2003) to 389 (2009) and was higher among women (p = 1.1 x 10⁻⁸), lower in older patients (p< 1 x 10⁻⁸) and lower in less developed regions (p = 1.864 x 10⁻⁵). Percentage of treated patients with undetectable viral loads increased linearly from 46% (2001) to 77% (2011), was lower among women (p = 2.851 x 10⁻⁶), younger ages (p = 1 x 10⁻³), and in less developed regions (p = 1.782 x 10⁻⁴). NRTI acquired resistance was 86% in 2001–3 and decreased over time. NNRTI resistance increased from 2001-3(50%) to 2006–9 (60%), PI resistance decreased from 2001–3 (60%) to 2009 (40%), and 3-class resistance was stable over time around 25%. Subtype prevalence comprised B (75.3%), B/F recombinants (12.2%), C (5.7%), F (5.3%) and B/C recombinants (1.5%), with regional variations. Three-class resistance was 26.5% among Bs, 22.4% among Fs and 17.2% among Cs.ConclusionsHIV diagnosis occurs late, especially among elderly Brazilians. Younger individuals need special attention due to poor virological response to treatment. Antiretroviral Resistance profile is subtype related.     

Linkage of HIV-Infected Infants from Diagnosis to Antiretroviral Therapy Services across the Western Cape,South Africa

Introduction

Early infant diagnosis (EID) of HIV infection is an important service to reduce paediatric morbidity and mortality related to HIV/AIDS. Although South Africa has a national EID programme based on PCR testing, there are no population-wide data on the linkage of infants testing HIV PCR-positive to HIV care and treatment services.

Methods

We conducted a retrospective analysis of all public sector laboratory data from across the Western Cape province between 2005 and 2011. We linked positive HIV PCR results to subsequent HIV viral load testing to determine the proportion of infants who were successfully linked to HIV care.

Results

A total of 83 698 unique infant HIV PCR tests were documented, of which 6322 (8%) were PCR positive. The proportion of PCR-positive children declined from 12% in 2005 to 3% in 2011. Of the children testing PCR-positive, 4105 (65%) had subsequent viral load testing indicating successful linkage to care. The proportion of successfully linked infants increased from 54% in 2005 to 71% in 2010, while the median delay in days to successful linkage decreased from 146 days in 2005 to 33 days in 2010.

Discussion

From 2005 to 2011 there has been a reduction in the proportion of children testing HIV PCR-positive, and an increase in the proportion of infected infants successfully linked to HIV care and treatment, in this setting. However a large proportion of infected infants remain unlinked to antiretroviral therapy services and there is a clear need for interventions to further strengthen EID programmes.     

Elimination of HIV in South Africa through Expanded Access to Antiretroviral Therapy: A Model Comparison Study

Background

Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study''s finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV.

Methods and Findings

We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study''s major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled.

Conclusions

Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination. Please see later in the article for the Editors'' Summary     

Effectiveness of Patient Adherence Groups as a Model of Care for Stable Patients on Antiretroviral Therapy in Khayelitsha,Cape Town,South Africa

Background

Innovative models of care are required to cope with the ever-increasing number of patients on antiretroviral therapy in the most affected countries. This study, in Khayelitsha, South Africa, evaluates the effectiveness of a group-based model of care run predominantly by non-clinical staff in retaining patients in care and maintaining adherence.

Methods and Findings

Participation in “adherence clubs” was offered to adults who had been on ART for at least 18 months, had a current CD4 count >200 cells/ml and were virologically suppressed. Embedded in an ongoing cohort study, we compared loss to care and virologic rebound in patients receiving the intervention with patients attending routine nurse-led care from November 2007 to February 2011. We used inverse probability weighting to estimate the intention-to-treat effect of adherence club participation, adjusted for measured baseline and time-varying confounders. The principal outcome was the combination of death or loss to follow-up. The secondary outcome was virologic rebound in patients who were virologically suppressed at study entry. Of 2829 patients on ART for >18 months with a CD4 count above 200 cells/µl, 502 accepted club participation. At the end of the study, 97% of club patients remained in care compared with 85% of other patients. In adjusted analyses club participation reduced loss-to-care by 57% (hazard ratio [HR] 0.43, 95% CI = 0.21–0.91) and virologic rebound in patients who were initially suppressed by 67% (HR 0.33, 95% CI = 0.16–0.67).

Discussion

Patient adherence groups were found to be an effective model for improving retention and documented virologic suppression for stable patients in long term ART care. Out-of-clinic group-based models facilitated by non-clinical staff are a promising approach to assist in the long-term management of people on ART in high burden low or middle-income settings.     

Monitoring of Antiretroviral Therapy and Mortality in HIV Programmes in Malawi,South Africa and Zambia: Mathematical Modelling Study

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.