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The need for second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030: a mathematical modelling study.

ABSTRACT: The number of patients in need of second-line antiretroviral drugs is increasing in sub-Saharan Africa. We aimed to project the need of second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030.We developed a simulation model for HIV and applied it to each sub-Saharan African country. We used the WHO country intelligence database to estimate the number of adult patients receiving antiretroviral therapy from 2005 to 2014. We fitted the number of adult patients receiving antiretroviral therapy to observed estimates, and predicted first-line and second-line needs between 2015 and 2030. We present results for sub-Saharan Africa, and eight selected countries. We present 18 scenarios, combining the availability of viral load monitoring, speed of antiretroviral scale-up, and rates of retention and switching to second-line. HIV transmission was not included.Depending on the scenario, 8·7-25·6 million people are expected to receive antiretroviral therapy in 2020, of whom 0·5-3·0 million will be receiving second-line antiretroviral therapy. The proportion of patients on treatment receiving second-line therapy was highest (15·6%) in the scenario with perfect retention and immediate switching, no further scale-up, and universal routine viral load monitoring. In 2030, the estimated range of patients receiving antiretroviral therapy will remain constant, but the number of patients receiving second-line antiretroviral therapy will increase to 0·8-4·6 million (6·6-19·6%). The need for second-line antiretroviral therapy was two to three times higher if routine viral load monitoring was implemented throughout the region, compared with a scenario of no further viral load monitoring scale-up. For each monitoring strategy, the future proportion of patients receiving second-line antiretroviral therapy differed only minimally between countries.Donors and countries in sub-Saharan Africa should prepare for a substantial increase in the need for second-line drugs during the next few years as access to viral load monitoring improves. An urgent need exists to decrease the costs of second-line drugs.World Health Organization, Swiss National Science Foundation, National Institutes of Health.

SUBMITTER: Estill J

PROVIDER: S-EPMC5688234 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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The need for second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030: a mathematical modelling study.

Estill Janne J Ford Nathan N Salazar-Vizcaya Luisa L Haas Andreas D AD Blaser Nello N Habiyambere Vincent V Keiser Olivia O

The lancet. HIV 20160216 3

<h4>Background</h4>The number of patients in need of second-line antiretroviral drugs is increasing in sub-Saharan Africa. We aimed to project the need of second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030.<h4>Methods</h4>We developed a simulation model for HIV and applied it to each sub-Saharan African country. We used the WHO country intelligence database to estimate the number of adult patients receiving antiretroviral therapy from 2005 to 2014. We fitted the number ...[more]

PMID: 26939736

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Project description:BackgroundMany individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality.MethodsTo assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART.FindingsThe use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14-20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6-30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8-49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67-3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually.InterpretationAs a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.

Project description:BackgroundThe proportion of heterosexual HIV transmission in sub-Saharan Africa that occurs within cohabiting partnerships, compared with that in single people or extra-couple relationships, is widely debated. We estimated the proportional contribution of different routes of transmission to new HIV infections. As plans to use antiretroviral drugs as a strategy for population-level prevention progress, understanding the importance of different transmission routes is crucial to target intervention efforts.MethodsWe built a mechanistic model of HIV transmission with data from Demographic and Health Surveys (DHS) for 2003-2011, of 27,201 cohabiting couples (men aged 15-59 years and women aged 15-49 years) from 18 sub-Saharan African countries with information about relationship duration, age at sexual debut, and HIV serostatus. We combined this model with estimates of HIV survival times and country-specific estimates of HIV prevalence and coverage of antiretroviral therapy (ART). We then estimated the proportion of recorded infections in surveyed cohabiting couples that occurred before couple formation, between couple members, and because of extra-couple intercourse.FindingsIn surveyed couples, we estimated that extra-couple transmission accounted for 27-61% of all HIV infections in men and 21-51% of all those in women, with ranges showing intercountry variation. We estimated that in 2011, extra-couple transmission accounted for 32-65% of new incident HIV infections in men in cohabiting couples, and 10-47% of new infections in women in such couples. Our findings suggest that transmission within couples occurs largely from men to women; however, the latter sex have a very high-risk period before couple formation.InterpretationBecause of the large contribution of extra-couple transmission to new HIV infections, interventions for HIV prevention should target the general sexually active population and not only serodiscordant couples.FundingUS National Institutes of Health, US National Science Foundation, and J S McDonnell Foundation.

Project description:BackgroundThe integrase inhibitor dolutegravir could have a major role in future antiretroviral therapy (ART) regimens in sub-Saharan Africa because of its high potency and barrier to resistance, good tolerability, and low cost, but there is uncertainty over appropriate policies for use relating to the potential for drug resistance spread and a possible increased risk of neural tube defects in infants if used in women at the time of conception. We used an existing individual-based model of HIV transmission, progression, and the effect of ART with the aim of informing policy makers on approaches to the use of dolutegravir that are likely to lead to the highest population health gains.MethodsWe used an existing individual-based model of HIV transmission and progression in adults, which takes into account the effects of drug resistance and differential drug potency in determining viral suppression and clinical outcomes to compare predicted outcomes of alternative ART regimen policies. We calculated disability adjusted life-years (DALYs) for each policy, assuming that a woman having a child with a neural tube defect incurs an extra DALY per year for the remainder of the time horizon and accounting for mother-to-child transmission. We used a 20 year time horizon, a 3% discount rate, and a cost-effectiveness threshold of US$500 per DALY averted.FindingsThe greatest number of DALYs is predicted to be averted with use of a policy in which tenofovir, lamivudine, and dolutegravir is used in all people on ART, including switching to tenofovir, lamivudine, and dolutegravir in those currently on ART, regardless of current viral load suppression and intention to have (more) children. This result was consistent in several sensitivity analyses. We predict that this policy would be cost-saving.InterpretationUsing a standard DALY framework to compare health outcomes from a public health perspective, the benefits of transition to tenofovir, lamivudine, and dolutegravir for all substantially outweighed the risks.FundingBill & Melinda Gates Foundation.

Project description:BackgroundIncreased second-line antiretroviral therapy (ART) failure rate narrows future options for HIV/AIDS treatment. It has critical implications in resource-limited settings; including sub-Saharan Africa (SSA) where the burden of HIV-infection is immense. Hence, pooled estimate for second-line HIV treatment failure is relevant to suggest valid recommendations that optimize ART outcomes in SSA.MethodsWe retrieved literature systematically from PUBMED/MEDLINE, EMBASE, CINAHL, Google Scholar, and AJOL. The retrieved studies were screened and assessed for eligibility. We also assessed the eligible studies for their methodological quality using the Joanna Briggs Institute's appraisal checklist. The pooled estimates for second-line HIV treatment failure and its associated factors were determined using STATA, version 15.0 and MEDCALC, version 18.11.3, respectively. We assessed publication bias using Comprehensive Meta-analysis software, version 3. Detailed study protocol for this review/meta-analysis is registered and found on PROSPERO (ID: CRD42018118959).ResultsA total of 33 studies with the overall 18,550 participants and 19,988.45 person-years (PYs) of follow-up were included in the review. The pooled second-line HIV treatment failure rate was 15.0 per 100 PYs (95% CI: 13.0-18.0). It was slightly higher at 12-18 months of follow-up (19.0/100 PYs; 95% CI: 15.0-22.0), in children (19.0/100 PYs; 95% CI: 14.0-23.0) and in southern SSA (18.0/100 PYs; 95% CI: 14.0-23.0). Baseline values (high viral load (OR: 5.67; 95% CI: 13.40-9.45); advanced clinical stage (OR: 3.27; 95% CI: 2.07-5.19); and low CD4 counts (OR: 2.80; 95% CI: 1.83-4.29)) and suboptimal adherence to therapy (OR: 1.92; 95% CI: 1.28-2.86) were the factors associated with increased failure rates.ConclusionSecond-line HIV treatment failure has become highly prevalent in SSA with alarming rates during the 12-18 month period of treatment start; in children; and southern SSA. Therefore, the second-line HIV treatment approach in SSA should critically consider excellent adherence to therapy, aggressive viral load suppression, and rapid immune recovery.

Project description:BACKGROUND:Substantial reductions in adult mortality have been observed in South Africa since the mid-2000s, but there has been no formal evaluation of how much of this decline is attributable to the scale-up of antiretroviral treatment (ART), as previous models have not been calibrated to vital registration data. We developed a deterministic mathematical model to simulate the mortality trends that would have been expected in the absence of ART, and with earlier introduction of ART. METHODS AND FINDINGS:Model estimates of mortality rates in ART patients were obtained from the International Epidemiology Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaboration. The model was calibrated to HIV prevalence data (1997-2013) and mortality data from the South African vital registration system (1997-2014), using a Bayesian approach. In the 1985-2014 period, 2.70 million adult HIV-related deaths occurred in South Africa. Adult HIV deaths peaked at 231,000 per annum in 2006 and declined to 95,000 in 2014, a reduction of 74.7% (95% CI: 73.3%-76.1%) compared to the scenario without ART. However, HIV mortality in 2014 was estimated to be 69% (95% CI: 46%-97%) higher in 2014 (161,000) if the model was calibrated only to HIV prevalence data. In the 2000-2014 period, the South African ART programme is estimated to have reduced the cumulative number of HIV deaths in adults by 1.72 million (95% CI: 1.58 million-1.84 million) and to have saved 6.15 million life years in adults (95% CI: 5.52 million-6.69 million). This compares with a potential saving of 8.80 million (95% CI: 7.90 million-9.59 million) life years that might have been achieved if South Africa had moved swiftly to implement WHO guidelines (2004-2013) and had achieved high levels of ART uptake in HIV-diagnosed individuals from 2004 onwards. The model is limited by its reliance on all-cause mortality data, given the lack of reliable cause-of-death reporting, and also does not allow for changes over time in tuberculosis control programmes and ART effectiveness. CONCLUSIONS:ART has had a dramatic impact on adult mortality in South Africa, but delays in the rollout of ART, especially in the early stages of the ART programme, have contributed to substantial loss of life. This is the first study to our knowledge to calibrate a model of ART impact to population-level recorded death data in Africa; models that are not calibrated to population-level death data may overestimate HIV-related mortality.

Project description:WHO recommends ritonavir-boosted protease inhibitor with two nucleoside reverse transcriptase inhibitors in HIV-infected patients failing non-nucleoside reverse transcriptase inhibitor-based first-line treatment. Here, we aimed to provide more evidence for the choice of nucleoside reverse transcriptase inhibitor and boosted protease inhibitor.ANRS 12169 is a 48-week, randomized, open-label, non-inferiority trial in three African cities, comparing efficacy and safety of three second-line regimens.Patients failing non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy with confirmed plasma HIV-1 viral load above 1000?copies/ml were randomly assigned to tenofovir/emtricitabine + lopinavir/ritonavir (control group as per WHO recommendations), abacavir + didanosine + lopinavir/ritonavir (ABC/ddI group) or tenofovir/emtricitabine + darunavir/ritonavir (DRV group) regimens. The primary endpoint was the proportion of patients with plasma vral load below 50?copies/ml at week 48 in the modified intention-to-treat population. Non-inferiority was pre-specified with a 15% margin.Of the 454 randomized patients, 451 were included in the analysis. Globally, 294 (65.2%) and 375 (83.2%) patients had viral load below 50 and 200?copies/ml, respectively, at week 48. The primary endpoint was achieved in 105 (69.1%) control group patients versus 92 (63.4%) in the ABC/ddI (difference 5.6%, 95% confidence interval -5.1 to 16.4) and 97 (63.0%) in the DRV (difference 6.1%, 95% confidence interval -4.5 to 16.7) groups (non-inferiority not shown). Overall, less number of patients with baseline viral load at least 100?000?copies/ml (n?=?122) had a viral load below 50?copies/ml at week 48 (37.7 versus 75.4%; P?<?0.001).The three second-line regimens obtained similar and satisfactory virologic control and confirmed the WHO recommendation (TDF/FTC/LPVr) as a valid option. However, the suboptimal response for patients with high viral load warrants research for improved strategies.

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The need for second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030: a mathematical modelling study.

Publications

The need for second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030: a mathematical modelling study.

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