Increasing insecticide resistance in Anopheles funestus and Anopheles arabiensis in Malawi, 2011-2015.

BACKGROUND: Susceptibility of principal Anopheles malaria vectors to common insecticides was monitored over a 5-year period across Malawi to inform and guide the national malaria control programme. METHODS: Adult blood-fed Anopheles spp. and larvae were collected from multiple sites in sixteen districts across the country between 2011 and 2015. First generation (F1) progeny aged 2-5 days old were tested for susceptibility, using standard WHO procedures, against pyrethroids (permethrin and deltamethrin), carbamates (bendiocarb and propoxur), organophosphates (malathion and pirimiphos-methyl) and an organochlorine (DDT). RESULTS: Mortality of Anopheles funestus to deltamethrin, permethrin, bendiocarb and propoxur declined significantly over the 5-year (2011-2015) monitoring period. There was wide variation in susceptibility to DDT but it was not associated with time. In contrast, An. funestus exhibited 100% mortality to the organophosphates (malathion and pirimiphos-methyl) at all sites tested. There was reduced mortality of Anopheles arabiensis to deltamethrin over time though this was not statistically significant. However, mortality of An. arabiensis exposed to permethrin declined significantly over time. Anopheles arabiensis exposed to DDT were more likely to be killed if there was high ITN coverage in the mosquito collection area the previous year. There were no other associations between mosquito mortality in a bioassay and ITN coverage or IRS implementation. Mortality of An. funestus from four sites exposed to deltamethrin alone ranged from 2 to 31% and from 41 to 94% when pre-exposed to the synergist piperonyl butoxide followed by deltamethrin. For permethrin alone, mortality ranged from 2 to 13% while mortality ranged from 63 to 100% when pre-exposed to PBO. CONCLUSION: Pyrethroid resistance was detected in An. funestus and An. arabiensis populations across Malawi and has worsened over the last 5 years. New insecticides and control strategies are urgently needed to reduce the burden of malaria in Malawi.

Prevalence and virologic consequences of transmitted HIV-1 drug resistance in Uganda.

Few reports have examined the impact of HIV-1 transmitted drug resistance (TDR) in resource-limited settings where there are fewer regimen choices and limited pretherapy/posttherapy resistance testing. In this study, we examined TDR prevalence in Kampala and Mbarara, Uganda and assessed its virologic consequences after antiretroviral therapy initiation. We sequenced the HIV-1 protease/reverse transcriptase from n=81 and n=491 treatment-naive participants of the Uganda AIDS Rural Treatment Outcomes (UARTO) pilot study in Kampala (AMU 2002-2004) and main cohort in Mbarara (MBA 2005-2010). TDR-associated mutations were defined by the WHO 2009 surveillance mutation list. Posttreatment viral load data were available for both populations. Overall TDR prevalence was 7% (Kampala) and 3% (Mbarara) with no significant time trend. There was a slight but statistically nonsignificant trend indicating that the presence of TDR was associated with a worse treatment outcome. Virologic suppression (≤400 copies/ml within 6 months posttherapy initiation) was achieved in 87% and 96% of participants with wildtype viruses versus 67% and 83% of participants with TDR (AMU, MBA p=0.2 and 0.1); time to suppression (log-rank p=0.3 and p=0.05). Overall, 85% and 96% of study participants achieved suppression regardless of TDR status. Surprisingly, among the TDR cases, approximately half still achieved suppression; the presence of pretherapy K103N while on nevirapine and fewer active drugs in the first regimen were most often observed with failures. The majority of patients benefited from the local HIV care system even without resistance monitoring. Overall, TDR prevalence was relatively low and its presence did not always imply treatment failure.

Quality of malaria case management in Malawi: results from a nationally representative health facility survey.

BACKGROUND: Malaria is endemic throughout Malawi, but little is known about quality of malaria case management at publicly-funded health facilities, which are the major source of care for febrile patients. METHODS: In April-May 2011, we conducted a nationwide, geographically-stratified health facility survey to assess the quality of outpatient malaria diagnosis and treatment. We enrolled patients presenting for care and conducted exit interviews and re-examinations, including reference blood smears. Moreover, we assessed health worker readiness (e.g., training, supervision) and health facility capacity (e.g. availability of diagnostics and antimalarials) to provide malaria case management. All analyses accounted for clustering and unequal selection probabilities. We also used survey weights to produce estimates of national caseloads. RESULTS: At the 107 facilities surveyed, most of the 136 health workers interviewed (83%) had received training on malaria case management. However, only 24% of facilities had functional microscopy, 15% lacked a thermometer, and 19% did not have the first-line artemisinin-based combination therapy (ACT), artemether-lumefantrine, in stock. Of 2,019 participating patients, 34% had clinical malaria (measured fever or self-reported history of fever plus a positive reference blood smear). Only 67% (95% confidence interval (CI): 59%, 76%) of patients with malaria were correctly prescribed an ACT, primarily due to missed malaria diagnosis. Among patients without clinical malaria, 31% (95% CI: 24%, 39%) were prescribed an ACT. By our estimates, 1.5 million of the 4.4 million malaria patients seen in public facilities annually did not receive correct treatment, and 2.7 million patients without clinical malaria were inappropriately given an ACT. CONCLUSIONS: Malawi has a high burden of uncomplicated malaria but nearly one-third of all patients receive incorrect malaria treatment, including under- and over-treatment. To improve malaria case management, facilities must at minimum have basic case management tools, and health worker performance in diagnosing malaria must be improved.

Patient-, health worker-, and health facility-level determinants of correct malaria case management at publicly funded health facilities in Malawi: results from a nationally representative health facility survey.

BACKGROUND: Prompt and effective case management is needed to reduce malaria morbidity and mortality. However, malaria diagnosis and treatment is a multistep process that remains problematic in many settings, resulting in missed opportunities for effective treatment as well as overtreatment of patients without malaria. METHODS: Prior to the widespread roll-out of malaria rapid diagnostic tests (RDTs) in late 2011, a national, cross-sectional, complex-sample, health facility survey was conducted in Malawi to assess patient-, health worker-, and health facility-level factors associated with malaria case management quality using multivariate Poisson regression models. RESULTS: Among the 2,019 patients surveyed, 34% had confirmed malaria defined as presence of fever and parasitaemia on a reference blood smear. Sixty-seven per cent of patients with confirmed malaria were correctly prescribed the first-line anti-malarial, with most cases of incorrect treatment due to missed diagnosis; 31% of patients without confirmed malaria were overtreated with an anti-malarial. More than one-quarter of patients were not assessed for fever or history of fever by health workers. The most important determinants of correct malaria case management were patient-level clinical symptoms, such as spontaneous complaint of fever to health workers, which increased both correct treatment and overtreatment by 72 and 210%, respectively (p<0.0001). Complaint of cough was associated with a 27% decreased likelihood of correct malaria treatment (p=0.001). Lower-level cadres of health workers were more likely to prescribe anti-malarials for patients, increasing the likelihood of both correct treatment and overtreatment, but no other health worker or health facility-level factors were significantly associated with case management quality. CONCLUSIONS: Introduction of RDTs holds potential to improve malaria case management in Malawi, but health workers must systematically assess all patients for fever, and then test and treat accordingly, otherwise, malaria control programmes might miss an opportunity to dramatically improve malaria case management, despite better diagnostic tools.

Free HIV antiretroviral therapy enhances adherence among individuals on stable treatment: implications for potential shortfalls in free antiretroviral therapy.

OBJECTIVE: To estimate the population-level causal effect of source of payment for HIV medication on treatment adherence using Marginal Structural Models. METHODS: Data were obtained from an observational cohort of 76 HIV-infected individuals with at least 24 weeks of antiretroviral therapy treatment from 2002 to 2007 in Kampala, Uganda. Adherence was the primary outcome and it was measured using the 30-day visual analogue scale. Marginal structural models (MSM) were used to estimate the effect of source of payment for HIV medication on adherence, adjusting for confounding by income, duration on antiretroviral therapy (ART), timing of visit, prior adherence, prior CD4⁺ T cell count and prior plasma HIV RNA. Traditional association models were also examined and the results compared. RESULTS: Free HIV treatment was associated with a 3.8% improvement in adherence in the marginal structural model, while the traditional statistical models showed a 3.1-3.3% improvement in adherence associated with free HIV treatment. CONCLUSION: Removing a financial barrier to treatment with ART by providing free HIV treatment appears to significantly improve adherence to antiretroviral therapy. With sufficient information on confounders, MSMs can be used to make robust inferences about causal effects in epidemiologic research.

Training needs assessment for clinicians at antiretroviral therapy clinics: evidence from a national survey in Uganda.

BACKGROUND: To increase access to antiretroviral therapy in resource-limited settings, several experts recommend "task shifting" from doctors to clinical officers, nurses and midwives. This study sought to identify task shifting that has already occurred and assess the antiretroviral therapy training needs among clinicians to whom tasks have shifted. METHODS: The Infectious Diseases Institute, in collaboration with the Ugandan Ministry of Health, surveyed health professionals and heads of antiretroviral therapy clinics at a stratified random sample of 44 health facilities accredited to provide this therapy. A sample of 265 doctors, clinical officers, nurses and midwives reported on tasks they performed, previous human immunodeficiency virus training, and self-assessment of knowledge of human immunodeficiency virus and antiretroviral therapy. Heads of the antiretroviral therapy clinics reported on clinic characteristics. RESULTS: Thirty of 33 doctors (91%), 24 of 40 clinical officers (60%), 16 of 114 nurses (14%) and 13 of 54 midwives (24%) who worked in accredited antiretroviral therapy clinics reported that they prescribed this therapy (p<0.001). Sixty-four percent of the people who prescribed antiretroviral therapy were not doctors. Among professionals who prescribed it, 76% of doctors, 62% of clinical officers, 62% of nurses and 51% of midwives were trained in initiating patients on antiretroviral therapy (p=0.457); 73%, 46%, 50% and 23%, respectively, were trained in monitoring patients on the therapy (p=0.017). Seven percent of doctors, 42% of clinical officers, 35% of nurses and 77% of midwives assessed that their overall knowledge of antiretroviral therapy was lower than good (p=0.001). CONCLUSION: Training initiatives should be an integral part of the support for task shifting and ensure that antiretroviral therapy is used correctly and that toxicity or drug resistance do not reverse accomplishments to date.

Longitudinal antiretroviral adherence in HIV+ Ugandan parents and their children initiating HAART in the MTCT-Plus family treatment model: role of depression in declining adherence over time.

We conducted a study to assess the effect of family-based treatment on adherence amongst HIV-infected parents and their HIV-infected children attending the Mother-To-Child-Transmission Plus program in Kampala, Uganda. Adherence was assessed using home-based pill counts and self-report. Mean adherence was over 94%. Depression was associated with incomplete adherence on multivariable analysis. Adherence declined over time. Qualitative interviews revealed lack of transportation money, stigma, clinical response to therapy, drug packaging, and cost of therapy may impact adherence. Our results indicate that providing ART to all eligible HIV-infected members in a household is associated with excellent adherence in both parents and children. Adherence to ART among new parents declines over time, even when patients receive treatment at no cost. Depression should be addressed as a potential barrier to adherence. Further study is necessary to assess the long-term impact of this family treatment model on adherence to ART in resource-limited settings.

Steady state bioequivalence of generic and innovator formulations of stavudine, lamivudine, and nevirapine in HIV-infected Ugandan adults.

BACKGROUND: Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune) or the corresponding brand formulations (Epivir, Zerit, and Viramune). METHODOLOGY/PRINCIPAL FINDINGS: An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC(0-12h) and C(max). Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8-1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine C(max), 1.3 (0.99-1.71) and AUC(0-12h), 1.1 (0.87-1.38); lamivudine C(max), 0.8 (0.63-0.98) and AUC(0-12h), 0.8 (0.65-0.99); and nevirapine C(max), 1.1 (0.95-1.23) and AUC(0-12h), 1.1 (0.95-1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters. CONCLUSIONS/SIGNIFICANT FINDINGS: These findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical.

Hepatotoxicity during nevirapine-based fixed-dose combination antiretroviral therapy in kampala, Uganda.

BACKGROUND: Generic, low-cost, nevirapine (NVP)-based antiretroviral therapy (ART) has improved survival in HIV-infected individuals living in resource-limited settings. However, there is concern about the potential hepatotoxicity of these regimens. METHODS: The authors conducted a prospective study of persons initiating self-pay Triomune or Maxivir therapy in Kampala, Uganda. RESULTS: The 97 study participants were predominantly women (64%), median age was 35 (interquartile range [IQR] 30-40), median CD4 at baseline was 56 cells/mm(3) (IQR 8-138), and 19% had lifetime alcohol problems (CAGE >/= 2). Severe liver enzyme elevations (LEEs) of grade 3-4 were rare (2.2%); however, 1 patient died in the setting of grade 4 LEEs. Grade 1-4 LEEs occurred among 22.2% of participants, and 9.8% had new grade 1-4 LEEs after the initiation of treatment. DISCUSSION: The authors found that LEEs were common but that severe hepatotoxicity in persons initiating NVP-based ART was infrequent yet potentially life-threatening. Monitoring for NVP-related severe hepatic toxicity should be part of expanding antiretroviral treatment programs in resource-limited settings.

Treatment interruptions predict resistance in HIV-positive individuals purchasing fixed-dose combination antiretroviral therapy in Kampala, Uganda.

OBJECTIVE: To evaluate adherence, treatment interruptions, and outcomes in patients purchasing antiretroviral fixed-dose combination (FDC) therapy. DESIGN: Ninety-seven participants were recruited into a prospective 24-week observational cohort study of HIV-positive, antiretroviral-naive individuals initiating self-pay Triomune or Maxivir therapy in Kampala, Uganda. Adherence was measured by monthly structured interview, unannounced home pill count, and electronic medication monitors (EMM). Treatment interruptions were measured as continuous intervals greater than 48 h without opening the EMM. The primary outcomes were survival with viral suppression below 400 copies/ml, CD4 cell increases, and genotypic drug resistance at 24 weeks. RESULTS: The median baseline CD4 cell count was 56 cells/microl and median log10 copies RNA/ml was 5.54; mean adherence ranged from 82 to 95% for all measures but declined significantly over time. In an intent-to-treat analysis, 70 (72%) patients had an undetectable plasma HIV-RNA level at week 24. Sixty-two of 95 (65%) individuals with continuous EMM data had a treatment interruption of greater than 48 h. Treatment interruptions accounted for 90% of missed doses. None of 33 participants who did not interrupt treatment for over 48 h had drug resistance, whereas eight of 62 (13%) participants who did interrupt therapy experienced drug resistance. Antiretroviral resistance was seen in 8% of individuals and overall mortality was 10% at 24 weeks. CONCLUSION: HIV-positive individuals purchasing generic FDC antiretroviral therapy have high rates of adherence and viral suppression, low rates of antiretroviral resistance, and robust CD4 cell responses. Adherence is an important predictor of survival with full viral suppression. Treatment interruptions are an important predictor of drug resistance.

Etiology of pruritic papular eruption with HIV infection in Uganda.

CONTEXT: A frequent cause of human immunodeficiency virus (HIV)-related morbidity in sub-Saharan Africa is a commonly occurring, intensely pruritic skin rash. The resulting scars are disfiguring and stigmatizing. Despite the substantial prevalence of pruritic papular eruption (PPE) among HIV-infected Africans, the cause has been elusive. OBJECTIVE: To determine the etiology of PPE occurring in HIV-infected individuals. DESIGN, SETTING, AND PATIENTS: Cross-sectional study of HIV-infected patients with active PPE from clinics in Uganda conducted from May 19 through June 6, 2003. Enrollment occurred in the month preceding May 19. Each participant was clinically examined by 2 dermatologists, had laboratory studies performed, was administered an epidemiologic questionnaire, and had a skin biopsy of a new lesion evaluated by a dermatopathologist. MAIN OUTCOME MEASURES: Histological characteristics of new pruritic lesions. Other assessments included CD4 cell count, eosinophil count, and physician-assessed rash severity. RESULTS: Of 109 patients meeting inclusion criteria, 102 (93.6%) completed the study. The CD4 cell counts in this study population were generally low (median, 46/microL) and inversely related to increasing rash severity (median CD4 cell counts: 122 for mild, 41 for moderate, and 9 for severe; P<.001 for trend). Eighty-six patients (84%; 95% confidence interval, 77%-91%) had biopsy findings characteristic of arthropod bites. Patients with arthropod bites on biopsy had significantly higher peripheral eosinophil counts (median, 330 vs 180/microL; P = .02) and had a trend toward lower CD4 cell counts (median, 40 vs 99/microL; P = .07) than those without histological evidence of arthropod bites. CONCLUSIONS: Pruritic papular eruption occurring in HIV-infected individuals may be a reaction to arthropod bites. We hypothesize that this condition reflects an altered and exaggerated immune response to arthropod antigens in a subset of susceptible HIV-infected patients.

Multiple validated measures of adherence indicate high levels of adherence to generic HIV antiretroviral therapy in a resource-limited setting.

BACKGROUND: There are no validated measures of adherence to HIV antiretroviral therapy in resource-poor settings. Such measures are essential to understand the unique barriers to adherence as access to HIV antiretroviral therapy expands. METHODS: We assessed correspondence between multiple measures of adherence and viral load suppression in 34 patients purchasing generic Triomune antiretroviral therapy (coformulated stavudine, lamivudine, and nevirapine; CIPLA, Ltd., Mumbai, India) in Kampala, Uganda. Measures included 3-day patient self-report, 30-day visual analog scale, electronic medication monitoring, and unannounced home pill count. HIV-1 load was determined at baseline and 12 weeks. RESULTS: Mean adherence was 91%-94% by all measures. Seventy-six percent of subjects had a viral load of <400 copies/mL at 12 weeks. All measures were closely correlated with each other (R = 0.77-0.89). Each measure was also significantly associated with 12-week HIV load. There was no significant difference between patient-reported and objective measures of adherence. CONCLUSIONS: This sample of patients purchasing generic HIV antiretroviral therapy has among the highest measured adherence reported to date. Patient-reported measures were closely associated with objective measures. The relative ease of administration of the 30-day visual analog scale suggests that this may be the preferred method to assess adherence in resource-poor settings.