Costs and cost-effectiveness of alternative tuberculosis management strategies in South Africa - implications for policy

Objective. To conduct an economic analysis of the Hlabisa community-based directly observed therapy management strategy for tuberculosis and to project costs of three alternative strategies.Setting. Hlabisa health district, Kwazulu-Natal, South Africa.Methods. An economic analysis comparing the current tuberculosis management strategy in Hlabisa with three alternative strategies (the Hlabisa strategy prior to 1991 based on hospitalisation, the national strategy and sanatorium care) in terms of costs to both health service and patient and of cost-effectiveness.Results. The current Hlabisa strategy was the most cost-effective (R3 799 per patient cured), compared with R98 307 for the strategy used prior to 1991, R9 940 for the national strategy, and R11 145 for sanatorium care. Between 71 % and 88% of treatment costs lie with the health service, and hospitalisation (R119 per day) is the most expensive item. Prolonged hospitalisation is extremely expensive, but community care is cheaper (community clinic visit, R28; community health worker visit, R7). The total cost of supervising a patient in the community under the current Hlabisa strategy was R503, equivalent to 4.2 days in hospital. Drug costs (R157) are equivalent to just 1.3 days in hospital.Conclusion. Cost to both health service and patient can be substantially reduced by using community-based directly observed therapy for tuberculosis, a strategy that is cheap and cost-effective in Hlabisa. These findings have important national implications, supporting the goals of the new tuberculosis control programme

Prevalence of infection with human herpesvirus 8/Kaposi's sarcoma herpesvirus in rural South Africa

Objective. To determine prevalence of infection with human herpesvirus 8 (HHV-8)/Kaposi's sarcoma herpesvirus (KSHY) and to gain some insight into possible transmission dynamics of this novel virus in South Africa.Methods. Stored, anonymous serum from 50 patients with a ~ sexually transmitted disease (STD), 50 adult medical ward _. patients (25 male, 25 female), and 36 paediatric ward patients in Hlabisa Hospital, KwaZulu-Natal, was screened by enzyme-linked immunosorbent assay (ELISA) for antibodies to the small capsid-related protein encoded by HHV-8/KSHY orf65. Antibodies to the latency-associated nuclear antigen (LANA) were measured by immunofluorescence, and sera that were reactive in the ELISA but negative by immunofluorescence were re-tested by Western blot against the recombinant orf65 protein to exclude nonspecific reactivity.Results. Overall, 47 patients tested positive (34.6%), 76 tested negative (55.9%) and 13 (95%) had indeterminate results. Among those with a definite result, prevalence was similar among males (47.2%) and females (52.8%) and increased in later adulthood « 18 months 375%,19 -120 months 385%, 15 - 34 years 32.1%, 35 - 69 years 62.8%). Prevalence was highest among medical patients (58-1%); among those with an STD it was 31.1% (P = 0-01), and among children it was 22.8% (P = 0.001). When age-adjusted, prevalence among medical patients (23.7%) was similar to that among patients with an STD.Conclusion. Prevalence of HHV-8/KSHY is high in this setting and transmission appears to be occurring in childhood as well as among adults. Larger  population-based studies are required to detail the transmission dynamics of HHSV8/KSHv

Research Article (New England Journal of Medicine) A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults

Background: Streptococcus pneumoniae is a leading and serious coinfection in  adults with human immunodeficiency virus (HIV) infection, particularly in Africa. Prevention of this disease by vaccination with the current 23-valent polysaccharide vaccine is suboptimal. Protein conjugate vaccines offer a further option for protection, but data on their clinical efficacy in adults are needed.Methods: In this double-blind, randomized, placebo-controlled clinical efficacy trial, we studied the efficacy of a 7-valent conjugate pneumococcal vaccine in predominantly HIV-infected Malawian adolescents and adults who had recovered from documented invasive pneumococcal disease. Two doses of vaccine were given 4 weeks apart. The primary end point was a further episode of pneumococcal infection caused by vaccine serotypes or serotype 6A.Results: From February 2003 through October 2007, we followed 496 patients (of whom 44% were male and 88% were HIV-seropositive) for 798 person-years of observation. There were 67 episodes of pneumococcal disease in 52 patients, all in the HIV-infected subgroup. In 24 patients, there were 19 episodes that were caused by vaccine serotypes and 5 episodes that were caused by the 6A serotype. Of these episodes, 5 occurred in the vaccine group and 19 in the placebo group, for a vaccine efficacy of 74% (95% confidence interval [CI], 30 to 90). There were 73 deaths from any cause in the vaccine group and 63 in the placebo group (hazard ratio in the vaccine group, 1.18; 95% CI, 0.84 to 1.66). The number of serious adverse events within 14 days after vaccination was significantly lower in the  vaccine group than in the placebo group (3 vs. 17, P = 0.002), and the number of minor adverse events was significantly higher in the vaccine group (41 vs. 13, P = 0.003).Conclusions: The 7-valent pneumococcal conjugate vaccine protected HIV-infected adults from recurrent pneumococcal infection caused by vaccine serotypes or serotype 6A. (Current Controlled Trials number, ISRCTN54494731.

Cost effectiveness analysis of clinically driven versus routine laboratory monitoring of antiretroviral therapy in Uganda and Zimbabwe.

BACKGROUND: Despite funding constraints for treatment programmes in Africa, the costs and economic consequences of routine laboratory monitoring for efficacy and toxicity of antiretroviral therapy (ART) have rarely been evaluated. METHODS: Cost-effectiveness analysis was conducted in the DART trial (ISRCTN13968779). Adults in Uganda/Zimbabwe starting ART were randomised to clinically-driven monitoring (CDM) or laboratory and clinical monitoring (LCM); individual patient data on healthcare resource utilisation and outcomes were valued with primary economic costs and utilities. Total costs of first/second-line ART, routine 12-weekly CD4 and biochemistry/haematology tests, additional diagnostic investigations, clinic visits, concomitant medications and hospitalisations were considered from the public healthcare sector perspective. A Markov model was used to extrapolate costs and benefits 20 years beyond the trial. RESULTS: 3316 (1660LCM;1656CDM) symptomatic, immunosuppressed ART-naive adults (median (IQR) age 37 (32,42); CD4 86 (31,139) cells/mm(3)) were followed for median 4.9 years. LCM had a mean 0.112 year (41 days) survival benefit at an additional mean cost of $765 [95$7386 [3277,dominated] per life-year gained and $7793 [4442,39179] per quality-adjusted life year gained. Routine toxicity tests were prominent cost-drivers and had no benefit. With 12-weekly CD4 monitoring from year 2 on ART, low-cost second-line ART, but without toxicity monitoring, CD4 test costs need to fall below$3.78 to become cost-effective (<3xper-capita GDP, following WHO benchmarks). CD4 monitoring at current costs as undertaken in DART was not cost-effective in the long-term. CONCLUSIONS: There is no rationale for routine toxicity monitoring, which did not affect outcomes and was costly. Even though beneficial, there is little justification for routine 12-weekly CD4 monitoring of ART at current test costs in low-income African countries. CD4 monitoring, restricted to the second year on ART onwards, could be cost-effective with lower cost second-line therapy and development of a cheaper, ideally point-of-care, CD4 test

The impact of different CD4 monitoring and switching strategies on mortality in HIV-infected African adults on antiretroviral therapy; an application of dynamic marginal structural models

In Africa, antiretroviral therapy (ART) is delivered with limited laboratory monitoring, often none. In 2003–2004, investigators in the Development of Antiretroviral Therapy in Africa (DART) Trial randomized persons initiating ART in Uganda and Zimbabwe to either laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). CD4 cell counts were measured every 12 weeks in both groups but were only returned to treating clinicians for management in the LCM group. Follow-up continued through 2008. In observational analyses, dynamic marginal structural models on pooled randomized groups were used to estimate survival under different monitoring-frequency and clinical/immunological switching strategies. Assumptions included no direct effect of randomized group on mortality or confounders and no unmeasured confounders which influenced treatment switch and mortality or treatment switch and time-dependent covariates. After 48 weeks of first-line ART, 2,946 individuals contributed 11,351 person-years of follow-up, 625 switches, and 179 deaths. The estimated survival probability after a further 240 weeks for post-48-week switch at the first CD4 cell count less than 100 cells/mm3 or non-Candida World Health Organization stage 4 event (with CD4 count <250) was 0.96 (95% confidence interval (CI): 0.94, 0.97) with 12-weekly CD4 testing, 0.96 (95% CI: 0.95, 0.97) with 24-weekly CD4 testing, 0.95 (95% CI: 0.93, 0.96) with a single CD4 test at 48 weeks (baseline), and 0.92 (95% CI: 0.91, 0.94) with no CD4 testing. Comparing randomized groups by 48-week CD4 count, the mortality risk associated with CDM versus LCM was greater in persons with CD4 counts of <100 (hazard ratio = 2.4, 95% CI: 1.3, 4.3) than in those with CD4 counts of ≥100 (hazard ratio = 1.1, 95% CI: 0.8, 1.7; interaction P = 0.04). These findings support a benefit from identifying patients immunologically failing first-line ART at 48 weeks

The virological durability of first-line ART among HIV-positive adult patients in resource limited settings without virological monitoring: a retrospective analysis of DART trial data.

BACKGROUND: Few low-income countries have virological monitoring widely available. We estimated the virological durability of first-line antiretroviral therapy (ART) after five years of follow-up among adult Ugandan and Zimbabwean patients in the DART study, in which virological assays were conducted retrospectively. METHODS: DART compared clinically driven monitoring with/without routine CD4 measurement. Annual plasma viral load was measured on 1,762 patients. Analytical weights were calculated based on the inverse probability of sampling. Time to virological failure, defined as the first viral load measurement ≥200 copies/mL after 48 weeks of ART, was analysed using Kaplan-Meier plots and Cox regression models. RESULTS: Overall, 65% of DART trial patients were female. Patients initiated first-line ART at a median (interquartile range; IQR) age of 37 (32-42) and with a median CD4 cell count of 86 (32-140). After 240 weeks of ART, patients initiating dual-class nucleoside reverse-transcriptase inhibitor (NRTI) -non-nucleoside reverse-transcriptase (NNRTI) regimens containing nevirapine + zidovudine + lamivudine had a lower incidence of virological failure than patients on triple-NRTI regimens containing tenofovir + zidovudine + lamivudine (21% vs 40%; hazard ratio (HR) =0.48, 95% CI:0.38-0.62; p < 0.0001). In multivariate analyses, female patients (HR = 0.79, 95% CI: 0.65-0.95; p = 0.02), older patients (HR = 0.73 per 10 years, 95% CI: 0.64-0.84; p < 0.0001) and patients with a higher pre-ART CD4 cell count (HR = 0.64 per 100 cells/mm3, 95% CI: 0.54-0.75; p < 0.0001) had a lower incidence of virological failure after adjusting for adherence to ART. No difference in failure rate between the two randomised monitoring strategies was observed (p= 0.25). CONCLUSIONS: The long-term durability of virological suppression on dual-class NRTI-NNRTI first-line ART without virological monitoring is remarkable and is enabled by high-quality clinical management and a consistent drug supply. To achieve higher rates of virological suppression viral-load-informed differentiated care may be required. TRIAL REGISTRATION: Prospectively registered on 18/10/2000 as ISRCTN13968779

Potential cost-effectiveness of community availability of tenofovir, lamivudine, and dolutegravir for HIV prevention and treatment in east, central, southern, and west Africa: a modelling analysis

BACKGROUND: Post-exposure prophylaxis (PEP) offers protection from HIV after condomless sex, but is not widely available in a timely manner in east, central, southern, and west Africa. To inform the potential pilot implementation of such an approach, we modelled the effect and cost-effectiveness of making PEP consisting of tenofovir, lamivudine, and dolutegravir (TLD) freely and locally available in communities without prescription, with the aim of enabling PEP use within 24 h of condomless sex. Free community availability of TLD (referred to as community TLD) might also result in some use of TLD as pre-exposure prophylaxis (PrEP) and as antiretroviral therapy for people living with HIV. METHODS: Using an existing individual-based model (HIV Synthesis), we explicitly modelled the potential positive and negative effects of community TLD. Through the sampling of parameter values we created 1000 setting-scenarios, reflecting the uncertainty in assumptions and a range of settings similar to those seen in east, central, southern, and west Africa (with a median HIV prevalence of 14·8% in women and 8·1% in men). For each setting scenario, we considered the effects of community TLD. TLD PEP was assumed to have at least 90% efficacy in preventing HIV infection after condomless sex with a person living with HIV. FINDINGS: The modelled effects of community TLD availability based on an assumed high uptake of TLD resulted in a mean reduction in incidence of 31% (90% range over setting scenarios, 6% increase to 57% decrease) over 20 years, with an HIV incidence reduction over 50 years in 91% of the 1000 setting scenarios, deaths averted in 55% of scenarios, reduction in costs in 92% of scenarios, and disability-adjusted life-years averted in 64% of scenarios with community TLD. Community TLD was cost-effective in 90% of setting scenarios and cost-saving (with disability-adjusted life-years averted) in 58% of scenarios. When only examining setting scenarios in which there was lower uptake of community TLD, community TLD is cost-effective in 92% of setting scenarios. INTERPRETATION: The introduction of community TLD, enabling greater PEP access, is a promising approach to consider further in pilot implementation projects. FUNDING: Bill & Melinda Gates Foundation to the HIV Modelling Consortium

Implementation of Antiretroviral Therapy for Life in Pregnant/Breastfeeding HIV+ Women (Option B+) Alongside Rollout and Changing Guidelines for ART Initiation in Rural Zimbabwe: The Lablite Project Experience.

BACKGROUND: Lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women (Option B+) was rolled out in Zimbabwe from 2014, with simultaneous raising of the CD4 treatment threshold to 500 cells per cubic millimeter in nonpregnant/breastfeeding adults and children 5 years and over. METHODS: Lablite is an implementation project in Zimbabwe, Malawi, and Uganda evaluating ART rollout. Routine patient-level data were collected for 6 months before and 12 months after Option B+ rollout at a district hospital and 3 primary care facilities in Zimbabwe (2 with outreach ART and 1 with no ART provision before Option B+). RESULTS: Between September 2013 and February 2015, there were 1686 ART initiations in the 4 facilities: 91% adults and 9% children younger than 15 years. In the 3 facilities with established ART, initiations rose from 300 during 6 months before Option B+ to 869 (2.9-fold) and 463 (1.5-fold), respectively, 0-6 months and 6-12 months after Option B+. Post-Option B+, an estimated 43% of pregnant/breastfeeding women needed ART for their own health, based on World Health Organization stage 3/4 or CD4 ≤350 per cubic millimeter (64% for CD4 ≤500). Seventy-four men (22%) and 123 nonpregnant/breastfeeding women (34%) initiated ART with CD4 >350 after the CD4 threshold increase. Estimated 12-month retention on ART was 79% (69%-87%) in Option B+ women (significantly lower in younger women, P = 0.01) versus 93% (91%-95%) in other adults (difference P < 0.001). CONCLUSIONS: There were increased ART initiations in all patient groups after implementation of World Health Organization 2013 guidelines. Retention of Option B+ women was poorer than retention of other adults; younger women require attention because they are more likely to disengage from care

Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial

Background Major protease mutations are rarely observed following failure with protease inhibitors (PI), and other viral determinants of failure to PI are poorly understood. We therefore characterized Gag-Protease phenotypic susceptibility in subtype A and D viruses circulating in East Africa following viral rebound on PIs. Methods Samples from baseline and treatment failure in patients enrolled in the second line LPV/r trial SARA underwent phenotypic susceptibility testing. Data were expressed as fold-change in susceptibility relative to a LPV-susceptible reference strain. Results We cloned 48 Gag-Protease containing sequences from seven individuals and performed drug resistance phenotyping from pre-PI and treatment failure timepoints in seven patients. For the six patients where major protease inhibitor resistance mutations did not emerge, mean fold-change EC50 to LPV was 4.07 fold (95% CI, 2.08–6.07) at the pre-PI timepoint. Following viral failure the mean fold-change in EC50 to LPV was 4.25 fold (95% CI, 1.39–7.11, p = 0.91). All viruses remained susceptible to DRV. In our assay system, the major PI resistance mutation I84V, which emerged in one individual, conferred a 10.5-fold reduction in LPV susceptibility. One of the six patients exhibited a significant reduction in susceptibility between pre-PI and failure timepoints (from 4.7 fold to 9.6 fold) in the absence of known major mutations in protease, but associated with changes in Gag: V7I, G49D, R69Q, A120D, Q127K, N375S and I462S. Phylogenetic analysis provided evidence of the emergence of genetically distinct viruses at the time of treatment failure, indicating ongoing viral evolution in Gag-protease under PI pressure. Conclusions Here we observe in one patient the development of significantly reduced susceptibility conferred by changes in Gag which may have contributed to treatment failure on a protease inhibitor containing regimen. Further phenotype-genotype studies are required to elucidate genetic determinants of protease inhibitor failure in those who fail without traditional resistance mutations whilst PI use is being scaled up globally