HIV drug resistance among adults initiating antiretroviral therapy in Uganda.

BACKGROUND: WHO revised their HIV drug resistance (HIVDR) monitoring strategy in 2014, enabling countries to generate nationally representative HIVDR prevalence estimates from surveys conducted using this methodology. In 2016, we adopted this strategy in Uganda and conducted an HIVDR survey among adults initiating or reinitiating ART. METHODS: A cross-sectional survey of adults aged ≥18 years initiating or reinitiating ART was conducted at 23 sites using a two-stage cluster design sampling method. Participants provided written informed consent prior to enrolment. Whole blood collected in EDTA vacutainer tubes was used for preparation of dried blood spot (DBS) specimens or plasma. Samples were shipped from the sites to the Central Public Health Laboratory (CPHL) for temporary storage before transfer to the Uganda Virus Research Institute (UVRI) for genotyping. Prevalence of HIVDR among adults initiating or reinitiating ART was determined. RESULTS: Specimens from 491 participants (median age 32 years and 61.5% female) were collected between August and December 2016. Specimens from 351 participants were successfully genotyped. Forty-nine had drug resistance mutations, yielding an overall weighted HIVDR prevalence of 18.2% with the highest noted for NNRTIs at 14.1%. CONCLUSIONS: We observed a high HIVDR prevalence for NNRTIs among adults prior to initiating or reinitiating ART in Uganda. This is above WHO's recommended threshold of 10% when countries should consider changing from NNRTI- to dolutegravir-based first-line regimens. This recommendation was adopted in the revised Ugandan ART guidelines. Dolutegravir-containing ART regimens are preferred for first- and second-line ART regimens.

Prevalence of viral load suppression, predictors of virological failure and patterns of HIV drug resistance after 12 and 48 months on first-line antiretroviral therapy: a national cross-sectional survey in Uganda.

OBJECTIVES: We implemented the WHO cross-sectional survey protocol to determine rates of HIV viral load (VL) suppression (VLS), and weighted prevalence, predictors and patterns of acquired drug resistance (ADR) in individuals with virological failure (VF) defined as VL ≥1000 copies/mL. METHODS: We enrolled 547 and 1064 adult participants on first-line ART for 12 (±3) months (ADR12) and ≥48 months (ADR48), respectively. Dried blood spots and plasma specimens were collected for VL testing and genotyping among the VFs. RESULTS: VLS was 95.0% (95% CI 93.4%-96.5%) in the ADR12 group and 87.9% (95% CI 85.0%-90.9%) in the ADR48 group. The weighted prevalence of ADR was 96.1% (95% CI 72.9%-99.6%) in the ADR12 and 90.4% (95% CI 73.6-96.8%) in the ADR48 group, out of the 30 and 95 successful genotypes in the respective groups. Initiation on a zidovudine-based regimen compared with a tenofovir-based regimen was significantly associated with VF in the ADR48 group; adjusted OR (AOR) 1.96 (95% CI 1.13-3.39). Independent predictors of ADR in the ADR48 group were initiation on a zidovudine-based regimen compared with tenofovir-based regimens, AOR 3.16 (95% CI 1.34-7.46) and ART duration of ≥82 months compared with <82 months, AOR 1.92 (95% CI 1.03-3.59). CONCLUSIONS: While good VLS was observed, the high prevalence of ADR among the VFs before they underwent the recommended three intensive adherence counselling (IAC) sessions followed by repeat VL testing implies that IAC prior to treatment switching may be of limited benefit in improving VLS.

Population-based monitoring of HIV drug resistance early warning indicators in Uganda: A nationally representative survey following revised WHO recommendations.

INTRODUCTION: With the scale-up of antiretroviral therapy (ART) there is a need to monitor programme performance to maximize ART efficacy and to prevent emergence of HIV drug resistance (HIVDR). In keeping with the elements of the World Health Organisation (WHO) guidance we carried out a nationally representative assessment of early warning indicators (EWI) at 304 randomly selected ART service outlets in Uganda. METHODS: Retrospective patient data was extracted for the six EWIs for HIVDR including; on-time antiretroviral (ARV) drug pick-up, patient retention on ART at 12 months, ART dispensing practices, ARV drug stock-outs, viral load suppression (VLS) and viral load (VL) testing completion. Point prevalence for each clinic and national aggregate prevalence with 95% confidence intervals (CI) for all clinics were estimated and facility performances were computed and association between EWIs and programmatic factors assessed using Fisher's Exact Test. RESULTS: Facilities meeting the EWI targets: on-time pill pick-up was 9.5%, more facilities in the north met this target (p = 0.040). Retention on ART at 12 months was 24.1%, facilities in Kampala region (p<0.001) and Specialized ART clinics (p = 0.01) performed better in this indicator. Pharmacy stock-outs was 33.6%, with more facilities in Kampala (p<0.001), specialized ART clinics (p<0.001) and private-for-profit (p<0.001) meeting this target. Dispensing practices was met by 100% of the facilities. VLS was met by 49.2% and 50.8% of facilities met VL completion target with facilities in central region performing better (p<0.001). National prevalence for the EWIs was: on-time pill pick-up 63.3% (CI: 58.9-67.8); retention on ART at 12 months 69.9% (CI: 63.8-76.0); dispensing practices 100.0%; VLS 85.2% (CI: 81.8-88.5) and VL completion, 60.7% (CI: 56.9-64.6). CONCLUSION: Dispensing practices in all facilities were in line with the national guidelines however, there still remains a challenge to long-term ART programmatic success in monitoring patient response to treatment, and maintaining patients on ART without interruptions arising due to poor patient adherence and as a consequence of ARV supply interruption. It is therefore of high importance that the national ART program ensures intensified follow-up for patients, ensuring uninterrupted supply of ARV drugs and increasing VL monitoring at treatment centres, in order to improve patient outcomes and avert preventable HIVDR.

Tenofovir resistance in early and long-term treated patients on first-line antiretroviral therapy in eight low-income and middle-income countries.

OBJECTIVE: We aimed to assess the frequency of tenofovir (TDF) resistance in people failing tenofovir/lamivudine or emtricitabine (XTC)/nonnucleotide reverse-transcriptase inhibitor-based first-line antiretroviral treatment (ART) using data from 15 nationally representative surveys of HIV drug resistance conducted between 2014 and 2018 in Cameroon, Guatemala, Honduras, Nicaragua, Senegal, Uganda, Vietnam and Zambia. METHODS: Prevalence of nucleoside reverse-transcriptase inhibitor resistance among participants with virological nonsuppression (viral load ≥1000 copies/ml) who had received TDF-based ART for 12-24 months (early ART group) and at least 40 months (long-term ART group) was assessed using Sanger sequencing and resistance was interpreted using the Stanford HIVdb algorithm. For each group, we estimated a pooled prevalence using random effect meta-analysis. RESULTS: Of 4677 participants enrolled in the surveys, 640 (13.7%) had virological nonsuppression, 431 (67.3%) were successfully genotyped and were included in the analysis; of those, 60.3% (260) were participants in the early ART group. Overall, 39.1, 57.9, 38.5 and 3.6% patients in the early ART group and 42.9, 69.3, 42.9 and 10.0% patients on long-term ART had resistance to TDF, XTC, TDF + XTC and TDF + XTC + zidovudine, respectively. Overall, tenofovir resistance was mainly due to K65R or K70E/G/N/A/S/T/Y115F mutations (79%) but also due to thymidine analogue mutations (21%) which arise from exposure to thymidine analogues but causing cross-resistance to TDF. CONCLUSION: Dual resistance to TDF + XTC occurred in more than 40% of the people with viral nonsuppression receiving tenofovir-based first-line ART, supporting WHO recommendation to optimize the nucleoside backbone in second-line treatment and cautioning against single drug substitutions in people with unsuppressed viral load.

Survival and associated factors among patients with oral squamous cell carcinoma (OSCC) in Mulago hospital, Kampala, Uganda.

BACKGROUND: Despite improvements in diagnosis and patient management, survival and prognostic factors of patients with oral squamous cell carcinoma (OSCC) remains largely unknown in most of Sub Saharan Africa. OBJECTIVE: To establish survival and associated factors among patients with oral squamous cell carcinoma treated at Mulago Hospital Complex, Kampala. METHODS: We conducted a retrospective cohort study among histologically confirmed oral squamous cell carcinoma (OSCC) patients seen at our centre from January 1st 2002 to December 31st 2011. Survival was analysed using Kaplan-Meier method and comparison between associated variables made using Log rank-test. Cox proportional hazards model was used to determine independent predictors of survival. P-values of less than 0.05 were considered statistically significant. RESULTS: A total of 384 patients (229 males and 155 females) were included in this analysis. The overall mean age was 55.2 (SD 4.1) years. The 384 patients studied contributed a total of 399.17 person-years of follow-up. 111 deaths were observed, giving an overall death rate of 27.81 per 100 person-years [95% CI; 22.97-32.65]. The two-year and five-year survival rates were 43.6% (135/384) and 20.7% (50/384), respectively. Tumours arising from the lip had the best five-year survival rate (100%), while tumours arising from the floor of the mouth, alveolus and the gingiva had the worst prognosis with five-year survival rates of 0%, 0% and 15.9%, respectively. Independent predictors of survival were clinical stage (p = 0.001), poorly differentiated histo-pathological grade (p <  0.001), male gender (p = 0.001), age > 55 years at time of diagnosis (p = 0.02) and moderately differentiated histo-pathological grade (p = 0.027). However, tobacco & alcohol consumption, tumour location and treatment group were not associated with survival (p > 0.05). CONCLUSIONS: The five-year survival rate of OSCC was poor at 20.7%. Male gender, late clinical stage at presentation, poor histo-pathological types and advanced age were independent prognostic factors of survival. Early detection through screening and prompt treatment could improve survival.

Virological Response and Antiretroviral Drug Resistance Emerging during Antiretroviral Therapy at Three Treatment Centers in Uganda.

BACKGROUND: With the scale-up of antiretroviral therapy (ART), monitoring programme performance is needed to maximize ART efficacy and limit HIV drug resistance (HIVDR). METHODS: We implemented a WHO HIVDR prospective survey protocol at three treatment centers between 2012 and 2013. Data were abstracted from patient records at ART start (T1) and after 12 months (T2). Genotyping was performed in the HIV pol region at the two time points. RESULTS: Of the 425 patients enrolled, at T2, 20 (4.7%) had died, 66 (15.5%) were lost to follow-up, 313 (73.6%) were still on first-line, 8 (1.9%) had switched to second-line, 17 (4.0%) had transferred out and 1 (0.2%) had stopped treatment. At T2, 272 out of 321 on first and second line (84.7%) suppressed below 1000 copies/ml and the HIV DR prevention rate was 70.1%, just within the WHO threshold of ≥ 70%. The proportion of participants with potential HIVDR was 20.9%, which is higher than the 18.8% based on pooled analyses from African studies. Of the 35 patients with mutations at T2, 80% had M184V/I, 65.7% Y181C, and 48.6% (54.8% excluding those not on Tenofovir) had K65R mutations. 22.9% had Thymidine Analogue Mutations (TAMs). Factors significantly associated with HIVDR prevention at T2 were: baseline viral load (VL) <100,000 copies/ml [Adjusted odds ratio (AOR) 3.13, 95% confidence interval (CI): 1.36-7.19] and facility. Independent baseline predictors for HIVDR mutations at T2 were: CD4 count < 250 cells/µl (AOR 2.80, 95% CI: 1.08-7.29) and viral load ≥ 100,000 copies/ml (AOR 2.48, 95% CI: 1.00-6.14). CONCLUSION: Strengthening defaulter tracing, intensified follow-up for patients with low CD4 counts and/or high VL at ART initiation together with early treatment initiation above 250 CD4 cells/ul and adequate patient counselling would improve ART efficacy and HIVDR prevention. The high rate of K65R and TAMs could compromise second line regimens including NRTIs.