Bernhard Kerschberger

The effect of complete integration of HIV and TB services on time to initiation of antiretroviral therapy: a before-after study.

Background Studies have shown that early ART initiation in TB/HIV co-infected patients lowers mortality. One way to implement earlier ART commencement could be through integration of TB and HIV services, a more efficient model of care than separate, vertical programs. We present a model of full TB/HIV integration and estimate its effect on time to initiation of ART. Methodology/Principal Findings We retrospectively reviewed TB registers and clinical notes of 209 TB/HIV co-infected adults with a CD4 count <250 cells/µl and registered for TB treatment at one primary care clinic in a South African township between June 2008 and May 2009. Using Kaplan-Meier and Cox proportional hazard analysis, we compared time between initiation of TB treatment and ART for the periods before and after full, “one-stop shop” integration of TB and HIV services (in December 2009). Potential confounders were determined a priori through directed acyclic graphs. Robustness of assumptions was investigated by sensitivity analyses. The analysis included 188 patients (100 pre- and 88 post-integration), yielding 56 person-years of observation. Baseline characteristics of the two groups were similar. Median time to ART initiation decreased from 147 days (95% confidence interval [CI] 85–188) before integration of services to 75 days (95% CI 52–119) post-integration. In adjusted analyses, patients attending the clinic post-integration were 1.60 times (95% CI 1.11–2.29) more likely to have started ART relative to the pre-integration period. Sensitivity analyses supported these findings. Conclusions/Significance Full TB/HIV care integration is feasible and led to a 60% increased chance of co-infected patients starting ART, while reducing time to ART initiation by an average of 72 days. Although these estimates should be confirmed through larger studies, they suggest that scale-up of full TB/HIV service integration in high TB/HIV prevalence settings may shorten time to ART initiation, which might reduce excess mortality and morbidity.

Feasibility and effectiveness of two community-based HIV testing models in rural Swaziland.

To evaluate the feasibility (population reached, costs) and effectiveness (positivity rates, linkage to care) of two strategies of community‐based HIV testing and counselling (HTC) in rural Swaziland.

Time to Initiation of Antiretroviral Therapy Among Patients With HIV-Associated Tuberculosis in Cape Town, South Africa

We studied the time interval between starting tuberculosis treatment and commencing antiretroviral treatment (ART) in HIV-infected patients (n = 1433; median CD4 count 71 cells per microliter, interquartile range: 32-132) attending 3 South African township ART services between 2002 and 2008. The overall median delay was 2.66 months (interquartile range: 1.58-4.17). In adjusted analyses, delays varied between treatment sites but were shorter for patients with lower CD4 counts and those treated in more recent calendar years. During the most recent period (2007-2008), 4.7%, 19.7%, and 51.1% of patients started ART within 2, 4, and 8 weeks of tuberculosis treatment, respectively. Operational barriers must be tackled to permit further acceleration of ART initiation as recommended by 2010 WHO ART guidelines.

Impact and programmatic implications of routine viral load monitoring in Swaziland.

Objective:To assess the programmatic quality (coverage of testing, counseling, and retesting), cost, and outcomes (viral suppression, treatment decisions) of routine viral load (VL) monitoring in Swaziland. Design:Retrospective cohort study of patients undergoing routine VL monitoring in Swaziland (October 1, 2012 to March 31, 2013). Results:Of 5563 patients eligible for routine VL testing monitoring in the period of study, an estimated 4767 patients (86%) underwent testing that year. Of 288 patients with detectable VL, 210 (73%) underwent enhanced adherence counseling and 202 (70%) had a follow-up VL within 6 months. Testing coverage was slightly lower in children, but coverage of retesting was similar between and age groups and sexes. Of those with a follow-up test, 126 (62%) showed viral suppression. The remaining 78 patients had World Health Organization–defined virologic failure; 41 (53%) were referred by the doctor for more adherence counseling, and 13 (15%) were changed to second-line therapy, equating to an estimated rate of 1.2 switches per 100 patient-years. Twenty-four patients (32%) were transferred out, lost to follow-up, or not reviewed by doctor. The “fully loaded” cost of VL monitoring was

Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub Saharan Africa: a retrospective multi-centre cohort study

35 per patient-year. Conclusions:Achieving good quality VL monitoring is feasible and affordable in resource-limited settings, although close supervision is needed to ensure good coverage of testing and counseling. The low rate of switch to second-line therapy in patients with World Health Organization–defined virologic failure seems to reflect clinician suspicion of ongoing adherence problems. In our study, the main impact of routine VL monitoring was reinforcing adherence rather than increasing use of second-line therapy.

Benefits and risks of rapid initiation of antiretroviral therapy

Summary Background HIV-1 drug resistance to older thymidine analogue nucleoside reverse transcriptase inhibitor drugs has been identified in sub-Saharan Africa in patients with virological failure of first-line combination antiretroviral therapy (ART) containing the modern nucleoside reverse transcriptase inhibitor tenofovir. We aimed to investigate the prevalence and correlates of thymidine analogue mutations (TAM) in patients with virological failure of first-line tenofovir-containing ART. Methods We retrospectively analysed patients from 20 studies within the TenoRes collaboration who had locally defined viral failure on first-line therapy with tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI; nevirapine or efavirenz) in sub-Saharan Africa. Baseline visits in these studies occurred between 2005 and 2013. To assess between-study and within-study associations, we used meta-regression and meta-analyses to compare patients with and without TAMs for the presence of resistance to tenofovir, cytosine analogue, or NNRTIs. Findings Of 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60·5 cells per μL [IQR 21·0–128·0] in patients with TAMS vs 95·0 cells per μL [37·0–177·0] in patients without TAMs; p=0·007) and were more likely to have tenofovir resistance (93 [81%] of 115 patients with TAMs vs 352 [59%] of 597 patients without TAMs; p<0·0001), NNRTI resistance (107 [93%] vs 462 [77%]; p<0·0001), and cytosine analogue resistance (100 [87%] vs 378 [63%]; p=0·0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0·64 (p<0·0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1·29 (1·13–1·47; p<0·0001) Interpretation TAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains.

Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration

Background: Recent attention has focused on the question of how quickly antiretroviral therapy (ART) should be started once HIV diagnosis is confirmed. We assessed whether rapid ART initiation improves patient outcomes. Methods: We searched five databases from inception up to August 2017. Rapid ART initiation was defined as initiation within 14 days of HIV diagnosis. Data were pooled using random effects meta-analysis. Results: Across the randomized trials, ART start on the same day increased viral suppression at 12 months [three trials: relative risk (RR) 1.17, 95% confidence interval (CI) 1.07–1.27], retention in care at 12 months (RR 1.11, 95% CI 0.99–1.26), and the likelihood of starting ART within 90 days (four trials: RR 1.35, 95% CI 1.13–1.62) and 12 months after eligibility was established (three trials: RR 1.17, 95% CI 1.07–1.27). There was a nonsignificant trend toward reduced mortality (three trials: RR 0.53, 95% CI 0.24–1.08), as well as reduced loss to follow-up at 12 months (2 trials: RR 0.66, 95% CI 0.42–1.04). In the observational studies, offering accelerated ART initiation resulted in a greater likelihood of having started ART within 3 months (two studies: RR 1.53, 95% CI 1.11–2.10). There was a trend toward an increased risk of being lost to follow-up at 6 months (three studies: RR 1.85, 95% CI 0.96–3.55). Conclusion: Accelerated ART initiation can lead to improved clinical outcomes and is likely to be of particular benefit in those settings where extensive patient preparation prior to starting ART results in long delays. These findings informed a WHO recommendation supporting accelerated ART initiation, including same day ART start.

Superior virologic and treatment outcomes when viral load is measured at 3 months compared to 6 months on antiretroviral therapy

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

Successes and challenges in optimizing the viral load cascade to improve antiretroviral therapy adherence and rationalize second-line switches in Swaziland

Routine viral load (VL) monitoring is utilized to assess antiretroviral therapy (ART) adherence and virologic failure, and it is currently scaled‐up in many resource‐constrained settings. The first routine VL is recommended as late as six months after ART initiation for early detection of sub‐optimal adherence. We aimed to assess the optimal timing of first VL measurement after initiation of ART.

Retention on ART and predictors of disengagement from care in several alternative community-centred ART refill models in rural Swaziland

As antiretroviral therapy (ART) is scaled up, more patients become eligible for routine viral load (VL) monitoring, the most important tool for monitoring ART efficacy. For HIV programmes to become effective, leakages along the VL cascade need to be minimized and treatment switching needs to be optimized. However, many HIV programmes in resource‐constrained settings report significant shortfalls.