OBJECTIVES: We aimed to assess the extent of treatment interruption caused by efavirenz-associated ADEs.
METHODS: A case-control study of efavirenz recipients who did, versus did not (control) develop adverse drug events (ADE), and who were matched for baseline CD4 + at a ratio of 1:1.3 was conducted. Antiretroviral -naïve patients who were started on efavirenz were followed up retrospectively, and their records scrutinized every month for 2 years. Demographic and clinical predictors of treatment interruption were computed using Cox proportional hazard models. Kaplan- Meier curves were plotted to assess time to treatment interruption for the two groups. Clinical endpoints were: i) efficacy -improved CD4 + counts and/or viral load (VL) suppression, ii) safety -absence of treatment-limiting toxicities, and iii) durability - no interruption until follow-up ended.
RESULTS: Both groups had comparable CD4 + counts at baseline (p = 0.15). At t = 24-months, VL in both groups were suppressed to undetectable levels (<20 copies/mL) while median CD4 + was 353 cells/µL (IQR: 249-460). The mean time on treatment was 23 months (95% CI, 22.3 -23.4) in the control group without ADE and 20 months (95% CI, 18.9 - 21.6) in the ADE group (p = 0.001). Kaplan-Meier plots demonstrated that 59.5% of patients who experienced ≥ 1 ADE versus 81% of those who did not experience any ADE were estimated to continue treatment for up to 24 months with no interruption (p = 0.001). Most interruptions to EFV treatment occurred in the presence of opportunistic infections and these were detected within the first 5 months of treatment initiation. Independent predictors which negatively impacted the dependent variable i.e., treatment durability, were intravenous drug use (adjusted hazard ratio, aHR 2.17, 95% CI, 1.03-4.61, p = 0.043), presence of ≥ 1 opportunistic infection(s) (aHR 2.2, 95% CI, 1.13-4.21, p = 0.021), and presence of ≥ 1 serious ADE(s) (aHR 4.18, 95% CI, 1.98-8.85, p = 0.00).
CONCLUSION: Efavirenz' role as the preferred first-line regimen for South-East Asia's resource-limited regions will need to be carefully tailored to suit the regional population. Findings have implications to policy-makers and clinicians, particularly for the treatment of patients who develop ADEs and opportunistic infections, and for intravenous drug user subgroups.
DISCUSSION: We present a summary of the current and novel TPT regimens, including current evidence of use with antiretroviral regimens (ART). We review challenges and opportunities to scale-up TB prevention within HIV programmes, including the use of differentiated care approaches and demand creation for effective TB/HIV services delivery. TB preventive vaccines and diagnostics, including optimal algorithms, while important topics, are outside of the focus of this commentary.
CONCLUSIONS: A number of new tools and strategies to make TPT a standard of care in HIV programmes have become available. The new TPT regimens are safe and effective and can be used with current ART, with attention being paid to potential drug-drug interactions between rifamycins and some classes of antiretrovirals. More research and development is needed to optimize TPT for small children, pregnant women and drug-resistant TB (DR-TB). Effective programmatic scale-up can be supported through context-adapted demand creation strategies and the inclusion of TPT in client-centred services, such as differentiated service delivery (DSD) models. Robust collaboration between the HIV and TB programmes represents a unique opportunity to ensure that TB, a preventable and curable condition, is no longer the number one cause of death in PLHIV.
METHODS: Factors associated with survival and failure were analyzed using Cox proportional hazards and discrete time conditional logistic models.
RESULTS: TDR, found in 60 (4.1%) of 1471 Asian treatment-naive patients, was one of the significant predictors of failure. Patients with TDR to >1 drug in their regimen were >3 times as likely to fail compared to no TDR.
CONCLUSIONS: TDR was associated with failure in the context of non-fully sensitive regimens. Efforts are needed to incorporate resistance testing into national treatment programs.
OBJECTIVE: To identify the optimal CD4 cell count at which cART should be initiated.
DESIGN: Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L.
SETTING: HIV clinics in Europe and the Veterans Health Administration system in the United States.
PATIENTS: 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis.
MEASUREMENTS: Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death.
RESULTS: Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death.
LIMITATIONS: CD4 cell count at cART initiation was not randomized. Residual confounding may exist.
CONCLUSION: Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.
METHODS: Children enrolled in the TREAT Asia Pediatric HIV Observational Database who had SM (weight-for-height or body mass index-for-age Z score less than -3) at ART initiation were analyzed. Generalized estimating equations were used to investigate poor weight recovery (weight-for-age Z score less than -3) and poor CD4% recovery (CD4% <25), and competing risk regression was used to analyze mortality and toxicity-associated treatment modification.
RESULTS: Three hundred fifty-five (11.9%) of 2993 children starting ART had SM. Their median weight-for-age Z score increased from -5.6 at ART initiation to -2.3 after 36 months. Not using trimethoprim-sulfamethoxazole prophylaxis at baseline was associated with poor weight recovery [odds ratio: 2.49 vs. using; 95% confidence interval (CI): 1.66-3.74; P < 0.001]. Median CD4% increased from 3.0 at ART initiation to 27.2 after 36 months, and 56 (15.3%) children died during follow-up. More profound SM was associated with poor CD4% recovery (odds ratio: 1.78 for Z score less than -4.5 vs. -3.5 to less than -3.0; 95% CI: 1.08-2.92; P = 0.023) and mortality (hazard ratio: 2.57 for Z score less than -4.5 vs. -3.5 to less than -3.0; 95% CI: 1.24-5.33; P = 0.011). Twenty-two toxicity-associated ART modifications occurred at a rate of 2.4 per 100 patient-years, and rates did not differ by malnutrition severity.
CONCLUSION: Trimethoprim-sulfamethoxazole prophylaxis is important for the recovery of weight-for-age in severely malnourished children starting ART. The extent of SM does not impede weight-for-age recovery or antiretroviral tolerability, but CD4% response is compromised in children with a very low weight-for-height/body mass index-for-age Z score, which may contribute to their high rate of mortality.