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Introduction ACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second‐line protease inhibitor (PI)‐based antiretroviral therapy (ART) from 10 low‐ and middle‐income countries (LMICs). Participants resistant to lopinavir (LPV) and/or multiple nucleotide reverse transcriptase inhibitors started on third‐line regimens that included raltegravir (RAL), darunavir/ritonavir (DRV/r) and/or etravirine (ETR) according to their resistance profiles. At 48 weeks, 87% of these participants achieved HIV‐1 RNA ≤200 copies/ml. We report here long‐term outcomes over 144 weeks. Methods Study participants were enrolled from 2013 to 2015, prior to the availability of dolutegravir in LMICs. “Extended Follow‐up” of the study started after the last participant enrolled had reached 48 weeks and included participants still on antiretroviral (ARV) regimens containing RAL, DRV/r and/or ETR at that time. RAL, DRV/r and ETR were provided for an additional 96 weeks (giving total follow‐up of ≥144 weeks), with HIV‐1 RNA measured at 48 and 96 weeks and CD4 count at 96 weeks after entry into Extended Follow‐up. Proportion of participants with HIV‐1 RNA ≤200 copies/ml was estimated every 24 weeks, using imputation if necessary to handle the different measurement schedule in Extended Follow‐up; mean CD4 count changes were estimated using loess regression. Results and Discussion Of 257 participants (38% females), at study entry, median CD4 count was 179 cells/mm3, and HIV‐1 RNA was 4.6 log10 copies/ml. Median follow‐up was 168 weeks (IQR: 156–204); 15 (6%) participants were lost to follow‐up and 9 (4%) died. 27/246 (11%), 26/246 (11%) and 13/92 (14%) of participants who started RAL, DRV/r and ETR, respectively, discontinued these drugs; only three due to adverse events. 87%, 86%, 83% and 80% of the participants had HIV‐1 RNA ≤200 copies/ml at weeks 48, 96, 144 and 168 (95% CI at week 168: 74–85%), respectively. Mean increase from study entry in CD4 count at week 168 was 265 cells/mm3 (95% CI 247–283). Conclusions Third‐line regimens comprising of RAL, DRV/r and/or ETR were very well tolerated and had high rates of durable virologic suppression among PLWH in LMICs who were failing on second‐line PI‐based ART prior to the availability of dolutegravir.

To analyze the patterns and risk factors of HIV drug resistance mutations among patients failing second-line treatment and to describe early treatment responses to recommended third-line antiretroviral therapy (ART) in a national referral HIV clinic in Zimbabwe. Patients on boosted protease inhibitor (PI) regimens for more than 6 months with treatment failure confirmed by 2 viral load (VL) tests >1000 copies/mL were genotyped, and susceptibility to available antiretroviral drugs was estimated by the Stanford HIVdb program. Risk factors for major PI resistance were assessed by logistic regression. Third-line treatment was provided as Darunavir/r, Raltegravir, or Dolutegravir and Zidovudine, Abacavir Lamivudine, or Tenofovir. Genotypes were performed on 86 patients who had good adherence to treatment. The median duration of first- and second-line ART was 3.8 years (interquartile range [IQR], 2.3-5.1) and 2.6 years (IQR, 1.6-4.9), respectively. The median HIV viral load and CD4 cell count were 65 210 copies/mL (IQR, 8728-208 920 copies/mL) and 201 cells/mm (IQR, 49-333 cells/mm ). Major PI resistance-associated mutations (RAMs) were demonstrated in 44 (51%) non-nucleoside reverse transcriptase inhibitor RAMs in 72 patients (83%) and nucleoside reverse transcriptase inhibitors RAMs in 62 patients (72%). PI resistance was associated with age >24 years ( = .003) and CD4 cell count <200 cells/mm ( = .007). In multivariable analysis, only age >24 years was significantly associated (adjusted odds ratio, 4.75; 95% confidence interval, 1.69-13.38; = .003) with major PI mutations. Third-line DRV/r- and InSTI-based therapy achieved virologic suppression in 29/36 patients (81%) after 6 months. The prevelance of PI mutations was high. Adolescents and young adults had a lower risk of acquiring major PI resistance mutations, possibly due to poor adherence to ART. Third-line treatment with a regimen of Darunavir/r, Raltegravir/Dolutegravir, and optimized nucleoside reverse transcriptase inhibitors was effective.

Background While efficacy data exist, there are limited data on the outcomes of patients on third-line antiretroviral therapy (ART) in sub-Saharan Africa in actual practice. Being able to identify predictors of switch to third-line ART will be essential for planning for future need. We identify predictors of switch to third-line ART among patients with significant viraemia on a protease inhibitor (PI)-based second-line ART regimen. Additionally, we describe characteristics of all patients on third-line at a large public sector HIV clinic and present their early outcomes. Methods Retrospective analysis of adults (≥ 18 years) on a PI-based second-line ART regimen at Themba Lethu Clinic, Johannesburg, South Africa as of 01 August 2012, when third-line treatment became available in South Africa, with significant viraemia on second-line ART (defined as at least one viral load ≥ 1000 copies/mL on second-line ART after 01 August 2012) to identify predictors of switch to third-line (determined by genotype resistance testing). Third-line ART was defined as a regimen containing etravirine, raltegravir or ritonavir boosted darunavir, between August 2012 and January 2016. To assess predictors of switch to third-line ART we used Cox proportional hazards regression among those with significant viraemia on second-line ART after 01 August 2012. Then among all patients on third-line ART we describe viral load suppression, defined as a viral load < 400 copies/mL, after starting third-line ART. Results Among 719 patients in care and on second-line ART as of August 2012 (with at least one viral load ≥ 1000 copies/mL after 01 August 2012), 36 (5.0% over a median time of 54 months) switched to third-line. Time on second-line therapy (≥ 96 vs. < 96 weeks) (adjusted Hazard Ratio (aHR): 2.53 95% CI 1.03–6.22) and never reaching virologic suppression while on second-line ART (aHR: 3.37 95% CI 1.47–7.73) were identified as predictors of switch. In a separate cohort of patients on third-line ART, 78.3% (47/60) and 83.3% (35/42) of those in care and with a viral load suppressed their viral load at 6 and 12 months, respectively. Conclusions Our results show that the need for third-line is low (5%), but that patients’ who switch to third-line ART have good early treatment outcomes and are able to suppress their viral load. Adherence counselling and resistance testing should be prioritized for patients that are at risk of failure, in particular those who never suppress on second-line and those who have been on PI-based regimen for extended periods.

Background: South Africa’s antiretroviral therapy (ART) programme is the largest globally and the universal test-and-treat policy is expected to increase the numbers on ART. This may have implications for treatment failure rates implying a greater future need for third-line regimens. South Africa initiated a third-line programme in 2013. However, there is little evidence quantifying the third-line need in this setting and the programme itself has not been formally evaluated. Objectives: The study evaluated the third-line ART referral process in the Western Cape. Method: Routinely collected data were analysed to derive an estimate of patients meeting criteria for third-line referral and compared with patients who were referred. Factors associated with referral were identified. Results: In the study period, 947 patients met criteria for third-line referral and 167 patients were referred. Comparison revealed a poor overlap of only 42 patients. In multivariate analysis, factors associated with referral included receiving care at a hospital rather than a primary healthcare facility (adjusted odd ratios [aOR] = 2.15, 95% confidence interval [CI] 1.1–4.2), a higher number of viral load [VLs] ≥ 1000 copies/mL whilst on a protease inhibitor (PI) (aOR = 1.2, 95% CI 1.01–1.42) and a greater number of years on a PI (aOR = 1.25, 95% CI 1.07–1.46). Patients with a 6-month gap in dispensing were less likely to be referred (aOR = 0.37, 95% CI 0.17–0.81). Conclusion: This study adds to a limited body of knowledge regarding third-line ART programmes. The findings indicate missed opportunities for and inappropriate referral of patients. Factors associated with referral were largely health system related. Clinician awareness and compliance with referral remain unknown and may be contributory.

South Africa's antiretroviral therapy (ART) programme is the largest globally and the universal test-and-treat policy is expected to increase the numbers on ART. This may have implications for treatment failure rates implying a greater future need for third-line regimens. South Africa initiated a third-line programme in 2013. However, there is little evidence quantifying the third-line need in this setting and the programme itself has not been formally evaluated. The study evaluated the third-line ART referral process in the Western Cape. Routinely collected data were analysed to derive an estimate of patients meeting criteria for third-line referral and compared with patients who were referred. Factors associated with referral were identified. In the study period, 947 patients met criteria for third-line referral and 167 patients were referred. Comparison revealed a poor overlap of only 42 patients. In multivariate analysis, factors associated with referral included receiving care at a hospital rather than a primary healthcare facility (adjusted odd ratios [aOR] = 2.15, 95% confidence interval [CI] 1.1-4.2), a higher number of viral load [VLs] ≥ 1000 copies/mL whilst on a protease inhibitor (PI) (aOR = 1.2, 95% CI 1.01-1.42) and a greater number of years on a PI (aOR = 1.25, 95% CI 1.07-1.46). Patients with a 6-month gap in dispensing were less likely to be referred (aOR = 0.37, 95% CI 0.17-0.81). This study adds to a limited body of knowledge regarding third-line ART programmes. The findings indicate missed opportunities for and inappropriate referral of patients. Factors associated with referral were largely health system related. Clinician awareness and compliance with referral remain unknown and may be contributory.

Treatment failure continues to be an impediment to the efficacy of highly active antiretroviral therapy (HART) in the treatment of human immunodeficiency virus type 1 infection (HIV-1). The World Health Organization (WHO) recommends third-line antiretroviral therapy (ART) for patients who have failed second-line ART. Darunavir (DRV) boosted with ritonavir (DRV/r) has a higher genetic barrier to resistance, is active against multidrug-resistant HIV isolates, retaining virological activity even when multiple protease mutations are present, and has been shown to be cost-effective when compared to other boosted protease inhibitors (PIs). This is a case of a 40-year-old female known HIV/AIDS patient who has been on ART for the last 14 years with good adherence and regular follow-up, and who is now on 3rd line ART medication with TLD (tenofovir/lamivudine/dolutegravir)+DRV/r (in her 11th month) after being diagnosed with second-line treatment failure. After 6 months and 1 week of therapy, the viral load (VL) was sent, and the result was undetectable. The patient's clinical conditions had greatly improved. Third-line ART therapy, which was once thought to be a salvageable treatment, is now the primary option for second-line ART failure. TLD in combination with ritonavir-boosted darunavir is found to be effective at lowering viral loads in the blood below detectable limits. Despite a lack of data on the use of third-line ART in Ethiopia, access to third-line ART containing ritonavir-boosted darunavir is recommended because it has been shown to be an effective alternative for patients who have failed second-line ART. We recommend that more research be done with a larger sample size, and that the findings in this paper be used with caution.

Background HIV/AIDS has left a profound impact, leading to significant mortality, morbidity, economic strain, and disability on a global scale. The introduction of antiretroviral therapy (ART) has played a pivotal role in mitigating the economic burden of HIV and enhancing overall productivity. However, the emergence of virological failure presents a critical contemporary challenge within global health, reflecting the complexity of effectively managing HIV treatment outcomes in the 21st century. Methods An institutional based, cross-sectional study was conducted. Data were collected using a pretested, structured checklist. Data were edited and cleaned using Microsoft Excel 2016 and analyzed using SPSS version 25. Baseline demographic and clinical data were summarized using descriptive statistics. Multiple logistic regression analysis was run to identify association between dependent and independent variables, by computing odds ratio and 95% confidence interval. A p-value < 0.05 was considered significant. Results The study delved into the health profile of 117 individuals who were receiving treatment with a third-line antiretroviral therapy (ART) regimen. The findings revealed that the median age of the participants stood at 44 (IQR = ± 17) years and male accounted 53%. The median duration of after HIV diagnosis was found to be 14.25 (± IQR = 5.71) years. Overall virological suppression after third line ART was 76.9% at 6 months. Following adjustment with multiple variable logistic regression, good adherence to medication showed statistical significance in achieving virologic suppression (AOR = 8.48(95% CI: 2.3–30.8), p  = 0.001). In contrast, the absence of a change in the second line regimen (AOR = 3.0(95% CI: 0.36–24.8), p  = 0.31) and receiving second-line medication for less than three years (AOR = 1.07(95% CI: 0.39–2.95), p  = 0.89), and baseline viral load above 100,000 (AOR = 1.74(0.64–2.95), p  = 0.27) shows statistically non-significant association with virologic suppression. Clinical trial number: Not applicable. Conclusion This multicenter study provides strong evidence on virological suppression following the use of third-line antiretroviral therapy drugs in Ethiopia. The results of the study indicate rate of Virological suppression after starting third-line ART drugs is significantly linked to good adherence.

Established antiretroviral therapy (ART) programs in sub-Saharan Africa have well-defined first-and second-line therapies but no standard third-line ART regimen. The impact of third-line ART on patients with multiclass-resistant HIV in resource-limited settings has not been well characterized. We conducted a retrospective review of patients on third-line ART at the University Teaching Hospital in Lusaka, Zambia. We assessed virologic and immunologic outcomes following 6 months of third-line therapy and found among those with a documented viral load, viral suppression (≤1000 copies/ml) at 24 weeks was 95% (63/66) with a mean increase in CD4 count of 116 cells/mm3 and viral suppression of 63% (63/100) by imputation of missing data. This study suggests that third-line therapy is clinically and virologically effective among patients with multiclass-resistance in a resource-limited setting in sub-Saharan Africa.