Journal Article > Meta-AnalysisFull Text
PLOS One. 2013 July 22; Volume 8 (Issue 7); e68995.; DOI:10.1371/journal.pone.0068995
Pillay P, Ford NP, Shubber Z, Ferrand RA
PLOS One. 2013 July 22; Volume 8 (Issue 7); e68995.; DOI:10.1371/journal.pone.0068995
INTRODUCTION
There is conflicting evidence and practice regarding the use of the non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz (EFV) and nevirapine (NVP) in first-line antiretroviral therapy (ART).
METHODS
We systematically reviewed virological outcomes in HIV-1 infected, treatment-naive patients on regimens containing EFV versus NVP from randomised trials and observational cohort studies. Data sources include PubMed, Embase, the Cochrane Central Register of Controlled Trials and conference proceedings of the International AIDS Society, Conference on Retroviruses and Opportunistic Infections, between 1996 to May 2013. Relative risks (RR) and 95% confidence intervals were synthesized using random-effects meta-analysis. Heterogeneity was assessed using the I(2) statistic, and subgroup analyses performed to assess the potential influence of study design, duration of follow up, location, and tuberculosis treatment. Sensitivity analyses explored the potential influence of different dosages of NVP and different viral load thresholds.
RESULTS
Of 5011 citations retrieved, 38 reports of studies comprising 114 391 patients were included for review. EFV was significantly less likely than NVP to lead to virologic failure in both trials (RR 0.85 [0.73-0.99] I(2) = 0%) and observational studies (RR 0.65 [0.59-0.71] I(2) = 54%). EFV was more likely to achieve virologic success than NVP, though marginally significant, in both randomised controlled trials (RR 1.04 [1.00-1.08] I(2) = 0%) and observational studies (RR 1.06 [1.00-1.12] I(2) = 68%).
CONCLUSION
EFV-based first line ART is significantly less likely to lead to virologic failure compared to NVP-based ART. This finding supports the use of EFV as the preferred NNRTI in first-line treatment regimen for HIV treatment, particularly in resource limited settings.
There is conflicting evidence and practice regarding the use of the non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz (EFV) and nevirapine (NVP) in first-line antiretroviral therapy (ART).
METHODS
We systematically reviewed virological outcomes in HIV-1 infected, treatment-naive patients on regimens containing EFV versus NVP from randomised trials and observational cohort studies. Data sources include PubMed, Embase, the Cochrane Central Register of Controlled Trials and conference proceedings of the International AIDS Society, Conference on Retroviruses and Opportunistic Infections, between 1996 to May 2013. Relative risks (RR) and 95% confidence intervals were synthesized using random-effects meta-analysis. Heterogeneity was assessed using the I(2) statistic, and subgroup analyses performed to assess the potential influence of study design, duration of follow up, location, and tuberculosis treatment. Sensitivity analyses explored the potential influence of different dosages of NVP and different viral load thresholds.
RESULTS
Of 5011 citations retrieved, 38 reports of studies comprising 114 391 patients were included for review. EFV was significantly less likely than NVP to lead to virologic failure in both trials (RR 0.85 [0.73-0.99] I(2) = 0%) and observational studies (RR 0.65 [0.59-0.71] I(2) = 54%). EFV was more likely to achieve virologic success than NVP, though marginally significant, in both randomised controlled trials (RR 1.04 [1.00-1.08] I(2) = 0%) and observational studies (RR 1.06 [1.00-1.12] I(2) = 68%).
CONCLUSION
EFV-based first line ART is significantly less likely to lead to virologic failure compared to NVP-based ART. This finding supports the use of EFV as the preferred NNRTI in first-line treatment regimen for HIV treatment, particularly in resource limited settings.
Journal Article > ResearchFull Text
AIDS. 2019 August 1; Volume 33 (Issue 10); 1635-1644.; DOI:10.1097/QAD.0000000000002234
Shroufi A, van Cutsem G, Cambiano V, Bansi-Matharu L, Duncan K, et al.
AIDS. 2019 August 1; Volume 33 (Issue 10); 1635-1644.; DOI:10.1097/QAD.0000000000002234
BACKGROUND
Many 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.
METHODS
To 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.
FINDINGS
The 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.
INTERPRETATION
As 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.
Many 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.
METHODS
To 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.
FINDINGS
The 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.
INTERPRETATION
As 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.
Journal Article > Meta-AnalysisFull Text
AIDS. 2012 May 15; Volume 26 (Issue 8); DOI:10.1097/QAD.0b013e328351f5b2
Ajose O, Mookerjee S, Mills EJ, Boulle AM, Ford NP
AIDS. 2012 May 15; Volume 26 (Issue 8); DOI:10.1097/QAD.0b013e328351f5b2
A growing proportion of patients on antiretroviral therapy in resource-limited settings have switched to second-line regimens. We carried out a systematic review in order to summarize reported rates and reasons for virological failure among people on second-line therapy in resource-limited settings.
Journal Article > ResearchFull Text
Public Health Action. 2018 April 25; Volume 8 (Issue Suppl 1); S24-S28.; DOI:10.5588/pha.17.0019
Motlaleng M, Edwards JK, Namboze J, Butt W, Moakofhi K, et al.
Public Health Action. 2018 April 25; Volume 8 (Issue Suppl 1); S24-S28.; DOI:10.5588/pha.17.0019
BACKGROUND
Reliable information reporting systems ensure that all malaria cases are tested, treated and tracked to avoid further transmission. Botswana aimed to eliminate malaria by 2018, and surveillance is key. This study focused on assessing the uptake of the new malaria case-based surveillance (CBS) system introduced in 2012, which captures information on malaria cases reported in the Integrated Disease Surveillance and Response (IDSR) system.
METHODS
This was a retrospective descriptive study based on routine data focusing on Ngami, Chobe and Okavango, three high-risk districts in Botswana. Aggregated data variables were extracted from the IDSR and compared with data from the CBS.
RESULTS
The IDSR reported 456 malaria cases in 2013 and 1346 in 2014, of which respectively only 305 and 884 were reported by the CBS. The CBS reported 34% fewer cases than the IDSR system, indicating substantial differences between the two systems. The key malaria indicators with the greatest variability among the districts included in the study were case identification number and date of diagnosis.
CONCLUSION
The IDSR and CBS systems are essential for malaria elimination, as shown by the significant gaps in reporting between the two systems. These findings highlight the need for further investigation into these discrepancies. Strengthening the CBS system will help to reach the objective of malaria elimination in Botswana.
Reliable information reporting systems ensure that all malaria cases are tested, treated and tracked to avoid further transmission. Botswana aimed to eliminate malaria by 2018, and surveillance is key. This study focused on assessing the uptake of the new malaria case-based surveillance (CBS) system introduced in 2012, which captures information on malaria cases reported in the Integrated Disease Surveillance and Response (IDSR) system.
METHODS
This was a retrospective descriptive study based on routine data focusing on Ngami, Chobe and Okavango, three high-risk districts in Botswana. Aggregated data variables were extracted from the IDSR and compared with data from the CBS.
RESULTS
The IDSR reported 456 malaria cases in 2013 and 1346 in 2014, of which respectively only 305 and 884 were reported by the CBS. The CBS reported 34% fewer cases than the IDSR system, indicating substantial differences between the two systems. The key malaria indicators with the greatest variability among the districts included in the study were case identification number and date of diagnosis.
CONCLUSION
The IDSR and CBS systems are essential for malaria elimination, as shown by the significant gaps in reporting between the two systems. These findings highlight the need for further investigation into these discrepancies. Strengthening the CBS system will help to reach the objective of malaria elimination in Botswana.
Journal Article > ReviewFull Text
J Int AIDS Soc. 2012 October 9; Volume 15 (Issue 2); 17324.; DOI:10.7448/IAS.15.2.17324
Roberts TR, Bygrave H, Fajardo E, Ford NP
J Int AIDS Soc. 2012 October 9; Volume 15 (Issue 2); 17324.; DOI:10.7448/IAS.15.2.17324
Though the advantages of routine virological monitoring for patients on anti-retroviral therapy have been established, cost and complexity limit its full implementation. Monitoring is important for diagnosing virological failure early on, before the development of drug resistance mutations, and to trigger early adherence interventions. Simple and cost-effective viral load tests that facilitate simplification and decentralization of testing and strategies, such as the use of dried blood spots and pooled sample testing, which further aid simplification, are becoming available. In addition, replacing immunological monitoring with virological monitoring in non-viremic patients in a phased manner will reduce the costs associated with dual immuno-virological monitoring. Going forward, the simplification of testing paired with price reducing strategies that will allow for healthy competition between multiple manufacturers will enable the implementation of viral load testing in resource-poor settings. It is important that future HIV and AIDS treatment guidelines provide clear recommendations for routine virological monitoring and that governments and donors fund the implementation of accurate and operationally proven testing platforms in a comprehensive manner.
Journal Article > Meta-AnalysisFull Text
PLOS Med. 2011 January 1; Volume 8 (Issue 1); DOI:10.1371/journal.pmed.1000390
Egger M, Sidle J, Weigel R, Geng EH, Fox MP, et al.
PLOS Med. 2011 January 1; Volume 8 (Issue 1); DOI:10.1371/journal.pmed.1000390
The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART.
Journal Article > ResearchAbstract
AIDS Care. 2010 June 1; Volume 22 (Issue 6); DOI:10.1080/09540120903349102
Spaar A, Graber C, Dabis F, Coutsoudis A, Bachmann L, et al.
AIDS Care. 2010 June 1; Volume 22 (Issue 6); DOI:10.1080/09540120903349102
Expanded access to antiretroviral therapy (ART) offers opportunities to strengthen HIV prevention in resource-limited settings. We invited 27 ART programmes from urban settings in Africa, Asia and South America to participate in a survey, with the aim to examine what preventive services had been integrated in ART programmes. Twenty-two programmes participated; eight (36%) from South Africa, two from Brazil, two from Zambia and one each from Argentina, India, Thailand, Botswana, Ivory Coast, Malawi, Morocco, Uganda and Zimbabwe and one occupational programme of a brewery company included five countries (Nigeria, Republic of Congo, Democratic Republic of Congo, Rwanda and Burundi). Twenty-one sites (96%) provided health education and social support, and 18 (82%) provided HIV testing and counselling. All sites encouraged disclosure of HIV infection to spouses and partners, but only 11 (50%) had a protocol for partner notification. Twenty-one sites (96%) supplied male condoms, seven (32%) female condoms and 20 (91%) provided prophylactic ART for the prevention of mother-to child transmission. Seven sites (33%) regularly screened for sexually transmitted infections (STI). Twelve sites (55%) were involved in activities aimed at women or adolescents, and 10 sites (46%) in activities aimed at serodiscordant couples. Stigma and discrimination, gender roles and funding constraints were perceived as the main obstacles to effective prevention in ART programmes. We conclude that preventive services in ART programmes in lower income countries focus on health education and the provision of social support and male condoms. Strategies that might be equally or more important in this setting, including partner notification, prompt diagnosis and treatment of STI and reduction of stigma in the community, have not been implemented widely.
Journal Article > ResearchFull Text
NEJM Evid. 2023 September 1; Volume 2 (Issue 9); 1-12.; DOI:10.1056/EVIDoa2300054
Jindani A, Atwine D, Grint D, Bah B, Adams J, et al.
NEJM Evid. 2023 September 1; Volume 2 (Issue 9); 1-12.; DOI:10.1056/EVIDoa2300054
BACKGROUND
Shorter but effective tuberculosis treatment regimens would be of value to the tuberculosis treatment community. High-dose rifampicin has been associated with more rapid and secure lung sterilization and may enable shorter tuberculosis treatment regimens.
METHODS
We randomly assigned adults who were given a diagnosis of rifampicin-susceptible pulmonary tuberculosis to a 6-month control regimen, a similar 4-month regimen of rifampicin at 1200?mg/d (study regimen 1 [SR1]), or a 4-month regimen of rifampicin at 1800?mg/d (study regimen 2 [SR2]). Sputum specimens were collected at regular intervals. The primary end point was a composite of treatment failure and relapse in participants who were sputum smear positive at baseline. The noninferiority margin was 8 percentage points. Using a sequence of ordered hypotheses, noninferiority of SR2 was tested first.
RESULTS
Between January 2017 and December 2020, 672 patients were enrolled in six countries, including 191 in the control group, 192 in the SR1 group, and 195 in the SR2 group. Noninferiority was not shown. Favorable responses rates were 93, 90, and 87% in the control, SR1, and SR2 groups, respectively, for a country-adjusted absolute risk difference of 6.3 percentage points (90% confidence interval, 1.1 to 11.5) comparing SR2 with the control group. The proportions of participants experiencing a grade 3 or 4 adverse event were 4.0, 4.5, and 4.4% in the control, SR1, and SR2 groups, respectively.
CONCLUSIONS
Four-month high-dose rifampicin regimens did not have dose-limiting toxicities or side effects but failed to meet noninferiority criteria compared with the standard 6-month control regimen for treatment of pulmonary tuberculosis.
Shorter but effective tuberculosis treatment regimens would be of value to the tuberculosis treatment community. High-dose rifampicin has been associated with more rapid and secure lung sterilization and may enable shorter tuberculosis treatment regimens.
METHODS
We randomly assigned adults who were given a diagnosis of rifampicin-susceptible pulmonary tuberculosis to a 6-month control regimen, a similar 4-month regimen of rifampicin at 1200?mg/d (study regimen 1 [SR1]), or a 4-month regimen of rifampicin at 1800?mg/d (study regimen 2 [SR2]). Sputum specimens were collected at regular intervals. The primary end point was a composite of treatment failure and relapse in participants who were sputum smear positive at baseline. The noninferiority margin was 8 percentage points. Using a sequence of ordered hypotheses, noninferiority of SR2 was tested first.
RESULTS
Between January 2017 and December 2020, 672 patients were enrolled in six countries, including 191 in the control group, 192 in the SR1 group, and 195 in the SR2 group. Noninferiority was not shown. Favorable responses rates were 93, 90, and 87% in the control, SR1, and SR2 groups, respectively, for a country-adjusted absolute risk difference of 6.3 percentage points (90% confidence interval, 1.1 to 11.5) comparing SR2 with the control group. The proportions of participants experiencing a grade 3 or 4 adverse event were 4.0, 4.5, and 4.4% in the control, SR1, and SR2 groups, respectively.
CONCLUSIONS
Four-month high-dose rifampicin regimens did not have dose-limiting toxicities or side effects but failed to meet noninferiority criteria compared with the standard 6-month control regimen for treatment of pulmonary tuberculosis.
Journal Article > ResearchFull Text
Public Health Action. 2018 April 25; Volume 8 (Issue 1); DOI:10.5588/pha.17.0012
Obopile M, Segoea G, Waniwa K, Ntebela DS, Moakofhi K, et al.
Public Health Action. 2018 April 25; Volume 8 (Issue 1); DOI:10.5588/pha.17.0012
Setting: Larviciding has potential as a component of integrated vector management for the reduction of malaria transmission in Botswana by complementing long-lasting insecticide nets and indoor residual sprays. Objective: To evaluate the susceptibility of local Anopheles to commonly used larvicides. Design: This field test of the efficacy of Bacillus thuringiensis subsp. israliensis vs. Anopheles was performed by measuring larval density before treatment and 24 h and 48 h after treatment in seven sites of Bobirwa district, eastern Botswana, in 2012 and 2013. Vector density and malaria cases were compared between Bobirwa and Ngami (northwestern Botswana), with no larviciding in the control arm. Results: Larviciding reduced larval density by 95% in Bobirwa in 2012, with two cases of malaria, while in 2013 larval density reduction was 81%, with 11 cases. Adult mosquito density was zero for both years in Robelela village (Bobirwa), compared to respectively four and 26 adult mosquitoes per room in Shorobe village (Ngami) in 2012 and 2013. There were no cases of malaria in Robelela in either year, but in Shorobe there were 20 and 70 cases, respectively, in 2012 and 2013. Conclusion: Larviciding can reduce the larval density of mosquitoes and reduce malaria transmission in Botswana. Large-scale, targeted implementation of larviciding in districts at high risk for malaria is recommended.
Journal Article > Meta-AnalysisFull Text
AIDS. 2010 June 19; Volume 24 (Issue 10); DOI:10.1097/QAD.0b013e32833a2a14
Ford NP, Mofenson L, Kranzer K, Medu L, Frigati L, et al.
AIDS. 2010 June 19; Volume 24 (Issue 10); DOI:10.1097/QAD.0b013e32833a2a14
INTRODUCTION
Primate studies and some observational human data have raised concern regarding an association of first-trimester efavirenz exposure with central nervous system congenital anomalies. The objective of this review is to update evidence on efavirenz safety in HIV-infected pregnant women to inform revision of the 2013 WHO guidelines for antiretroviral therapy in low and middle-income countries.
DESIGN
A systematic review and meta-analysis.
METHODS
We searched for studies reporting birth outcomes among women exposed to efavirenz during the first trimester of pregnancy up to 10 January 2014. Relative risks of congenital anomalies comparing women exposed to efavirenz and nonefavirenz-based antiretroviral regimens were pooled using random effects meta-analysis.
RESULTS
Twenty-three studies were included in this review, among which 21 reported the birth outcomes of 2026 live births among women exposed to efavirenz during the first trimester of pregnancy. Forty-four congenital anomalies were reported, giving a pooled proportion of 1.63% [95% confidence interval (95% CI) 0.78-2.48], with only one neural tube defect. Twelve studies reported birth outcomes of women exposed to efavirenz or nonefavirenz-containing regimens during the first trimester of pregnancy. Pooled analysis found no differences in overall risks congenital anomalies between these two groups (relative risk 0.78, 95% CI 0.56-1.08). The incidence of neural tube defects was low, 0.05% (95% CI <0.01-0.28), and similar to incidence in the general population.
DISCUSSION
This updated analysis found no evidence of an increased risk of overall or central nervous system congenital anomalies associated with first-trimester exposure to efavirenz, similar to previous systematic reviews. This review contributed to the evidence base for the revised 2013 WHO guidelines on antiretroviral therapy, which recommend that efavirenz can be included as part of first-line therapy in adults regardless of sex, and that it can be used throughout pregnancy, including during the first trimester. However, because of the low incidence of central nervous system anomalies in the overall population and relatively small number of exposures in the current literature, continued birth outcomes prospective surveillance is warranted.
Primate studies and some observational human data have raised concern regarding an association of first-trimester efavirenz exposure with central nervous system congenital anomalies. The objective of this review is to update evidence on efavirenz safety in HIV-infected pregnant women to inform revision of the 2013 WHO guidelines for antiretroviral therapy in low and middle-income countries.
DESIGN
A systematic review and meta-analysis.
METHODS
We searched for studies reporting birth outcomes among women exposed to efavirenz during the first trimester of pregnancy up to 10 January 2014. Relative risks of congenital anomalies comparing women exposed to efavirenz and nonefavirenz-based antiretroviral regimens were pooled using random effects meta-analysis.
RESULTS
Twenty-three studies were included in this review, among which 21 reported the birth outcomes of 2026 live births among women exposed to efavirenz during the first trimester of pregnancy. Forty-four congenital anomalies were reported, giving a pooled proportion of 1.63% [95% confidence interval (95% CI) 0.78-2.48], with only one neural tube defect. Twelve studies reported birth outcomes of women exposed to efavirenz or nonefavirenz-containing regimens during the first trimester of pregnancy. Pooled analysis found no differences in overall risks congenital anomalies between these two groups (relative risk 0.78, 95% CI 0.56-1.08). The incidence of neural tube defects was low, 0.05% (95% CI <0.01-0.28), and similar to incidence in the general population.
DISCUSSION
This updated analysis found no evidence of an increased risk of overall or central nervous system congenital anomalies associated with first-trimester exposure to efavirenz, similar to previous systematic reviews. This review contributed to the evidence base for the revised 2013 WHO guidelines on antiretroviral therapy, which recommend that efavirenz can be included as part of first-line therapy in adults regardless of sex, and that it can be used throughout pregnancy, including during the first trimester. However, because of the low incidence of central nervous system anomalies in the overall population and relatively small number of exposures in the current literature, continued birth outcomes prospective surveillance is warranted.