Gender differences in immune reconstitution: a multicentric cohort analysis in sub-Saharan Africa

Background

In sub-Saharan Africa, men living with HIV often start ART at more advanced stages of disease and have higher early mortality than women. We investigated gender difference in long-term immune reconstitution.

Methods/Principal Findings

Antiretroviral-naïve adults who received ART for at least 9 months in four HIV programs in sub-Saharan Africa were included. Multivariate mixed linear models were used to examine gender differences in immune reconstitution on first line ART.A total of 21,708 patients (68% women) contributed to 61,912 person-years of follow-up. At ART start,. Median CD4 at ART were 149 [IQR 85–206] for women and 125 cells/µL [IQR 63–187] for men. After the first year on ART, immune recovery was higher in women than in men, and gender-based differences increased by 20 CD4 cells/µL per year on average (95% CI 16–23; P<0.001). Up to 6 years after ART start, patients with low initial CD4 levels experienced similar gains compared to patients with high initial levels, including those with CD4>250cells/µL (difference between patients with <50 cells/µL and those with >250 was 284 cells/µL; 95% CI 272–296; LR test for interaction with time p = 0.63). Among patients with initial CD4 count of 150–200 cells/µL, women reached 500 CD4 cells after 2.4 years on ART (95% CI 2.4–2.5) and men after 4.5 years (95% CI 4.1–4.8) of ART use.

Conclusion

Women achieved better long-term immune response to ART, reaching CD4 level associated with lower risks of AIDS related morbidity and mortality quicker than men.     

Integrated HIV testing, malaria, and diarrhea prevention campaign in Kenya: modeled health impact and cost-effectiveness

Background

Efficiently delivered interventions to reduce HIV, malaria, and diarrhea are essential to accelerating global health efforts. A 2008 community integrated prevention campaign in Western Province, Kenya, reached 47,000 individuals over 7 days, providing HIV testing and counseling, water filters, insecticide-treated bed nets, condoms, and for HIV-infected individuals cotrimoxazole prophylaxis and referral for ongoing care. We modeled the potential cost-effectiveness of a scaled-up integrated prevention campaign.

Methods

We estimated averted deaths and disability-adjusted life years (DALYs) based on published data on baseline mortality and morbidity and on the protective effect of interventions, including antiretroviral therapy. We incorporate a previously estimated scaled-up campaign cost. We used published costs of medical care to estimate savings from averted illness (for all three diseases) and the added costs of initiating treatment earlier in the course of HIV disease.

Results

Per 1000 participants, projected reductions in cases of diarrhea, malaria, and HIV infection avert an estimated 16.3 deaths, 359 DALYs and $85,113 in medical care costs. Earlier care for HIV-infected persons adds an estimated 82 DALYs averted (to a total of 442), at a cost of $37,097 (reducing total averted costs to $48,015). Accounting for the estimated campaign cost of $32,000, the campaign saves an estimated $16,015 per 1000 participants. In multivariate sensitivity analyses, 83% of simulations result in net savings, and 93% in a cost per DALY averted of less than $20.

Discussion

A mass, rapidly implemented campaign for HIV testing, safe water, and malaria control appears economically attractive.     

Predictors of poor CD4 and weight recovery in HIV-infected children initiating ART in South Africa

Objective

To identify baseline demographic and clinical risk factors associated with poor CD4 and weight response after initiation of antiretroviral therapy (ART) in a cohort of human immunodeficiency virus (HIV)-infected children in KwaZulu-Natal, South Africa.

Methods

We performed a retrospective cohort study of 674 children initiating antiretroviral therapy at McCord and St. Mary''s hospitals in KwaZulu-Natal, South Africa, from August 2003 to December 2008.We extracted data from paper charts and electronic medical records to assess risk factors associated with CD4 and weight response using logistic regression.

Results

From the initial cohort of 901 children <10 years old initiating ART between August 2003 and December 2008, we analyzed 674 children with complete baseline data. Viral suppression rates (<400 copies/ml) were 84% after six months of therapy and 88% after 12 months of therapy. Seventy-three percent of children achieved CD4 recovery after six months and 89% after 12 months. Weight-for-age Z-score (WAZ) improvements were seen in 58% of children after six months of ART and 64% after 12 months. After six months of ART, lower baseline hemoglobin (p = 0.037), presence of chronic diarrhea (p = 0.007), and virologic failure (p = 0.046) were all associated with poor CD4 recovery by multivariate logistic regression. After 12 months of ART, poor CD4 recovery was associated with higher baseline CD4% (p = 0.005), chronic diarrhea (p = 0.02), and virologic failure (p<0.001). Age less than 3 years at ART initiation (p = 0.0003), higher baseline CD4% (p<0.001), and higher baseline WAZ (p<0.001) were all associated with poor WAZ improvements after 6 months by multivariate logistic regression.

Conclusion

The presence of chronic diarrhea at baseline, independent of nutritional status and viral response, predicts poor CD4 recovery. Age at initiation of ART is an important factor in early WAZ response to ART, while viral suppression strongly predicts CD4 recovery but not WAZ improvement.     

Risk factors associated with increased mortality among HIV infected children initiating antiretroviral therapy (ART) in South Africa

Objective

To identify demographic and clinical risk factors associated with mortality after initiation of antiretroviral therapy (ART) in a cohort of human immunodeficiency (HIV) infected children in KwaZulu-Natal, South Africa.

Methods

We performed a retrospective cohort study of 537 children initiating antiretroviral therapy at McCord Hospital in KwaZulu-Natal, South Africa. Data were extracted from electronic medical records and risk factors associated with mortality were assessed using Cox regression analysis.

Results

Overall there were 47 deaths from the cohort of 537 children initiating ART with over 991 child-years of follow-up (median 22 months on ART), yielding a mortality rate of 4.7 deaths per 100 child years on ART. Univariate analysis indicated that mortality was significantly associated with lower weight-for-age Z-score (p<0.0001), chronic diarrhea (p = 0.0002), lower hemoglobin (p = 0.002), age <3 years (p = 0.003), and CD4% <10% (p = 0.005). The final multivariable Cox proportional hazards mortality model found age less than 3 years (p = 0.004), CD4 <10% (p = 0.01), chronic diarrhea (p = 0.03), weight-for-age Z-score (<0.0001) and female gender as a covariate varying with time (p = 0.03) all significantly associated with mortality.

Conclusion

In addition to recognized risk factors such as young age and advanced immunosuppression, we found female gender to be significantly associated with mortality in this pediatric ART cohort. Future studies are needed to determine whether intrinsic biologic differences or socio-cultural factors place female children with HIV at increased risk of death following initiation of ART.     

Evaluation of portable point-of-care CD4 counter with high sensitivity for detecting patients eligible for antiretroviral therapy

Background

Accurate, inexpensive point-of-care CD4+ T cell testing technologies are needed that can deliver CD4+ T cell results at lower level health centers or community outreach voluntary counseling and testing. We sought to evaluate a point-of-care CD4+ T cell counter, the Pima CD4 Test System, a portable, battery-operated bench-top instrument that is designed to use finger stick blood samples suitable for field use in conjunction with rapid HIV testing.

Methods

Duplicate measurements were performed on both capillary and venous samples using Pima CD4 analyzers, compared to the BD FACSCalibur (reference method). The mean bias was estimated by paired Student''s t-test. Bland Altman plots were used to assess agreement.

Results

206 participants were enrolled with a median CD4 count of 396 (range; 18–1500). The finger stick PIMA had a mean bias of −66.3 cells/µL (95%CI −83.4−49.2, P<0.001) compared to the FACSCalibur; the bias was smaller at lower CD4 counts (0–250 cells/µL) with a mean bias of −10.8 (95%CI −27.3−+5.6, P = 0.198), and much greater at higher CD4 cell counts (>500 cells/µL) with a mean bias of −120.6 (95%CI −162.8, −78.4, P<0.001). The sensitivity (95%CI) of the Pima CD4 analyzer was 96.3% (79.1–99.8%) for a <250 cells/ul cut-off with a negative predictive value of 99.2% (95.1–99.9%).

Conclusions

The Pima CD4 finger stick test is an easy-to-use, portable, relatively fast device to test CD4+ T cell counts in the field. Issues of negatively-biased CD4 cell counts especially at higher absolute numbers will limit its utility for longitudinal immunologic response to ART. The high sensitivity and negative predictive value of the test makes it an attractive option for field use to identify patients eligible for ART, thus potentially reducing delays in linkage to care and ART initiation.     

Estimating the resources needed and savings anticipated from roll-out of adult male circumcision in Sub-Saharan Africa

Background

Trials in Africa indicate that medical adult male circumcision (MAMC) reduces the risk of HIV by 60%. MAMC may avert 2 to 8 million HIV infections over 20 years in sub-Saharan Africa and cost less than treating those who would have been infected. This paper estimates the financial and human resources required to roll out MAMC and the net savings due to reduced infections.

Methods

We developed a model which included costing, demography and HIV epidemiology. We used it to investigate 14 countries in sub-Saharan Africa where the prevalence of male circumcision was lower than 80% and HIV prevalence among adults was higher than 5%, in addition to Uganda and the Nyanza province in Kenya. We assumed that the roll-out would take 5 years and lead to an MC prevalence among adult males of 85%. We also assumed that surgery would be done as it was in the trials. We calculated public program cost, number of full-time circumcisers and net costs or savings when adjusting for averted HIV treatments. Costs were in USD, discounted to 2007. 95% percentile intervals (95% PI) were estimated by Monte Carlo simulations.

Results

In the first 5 years the number of circumcisers needed was 2 282 (95% PI: 2 018 to 2 959), or 0.24 (95% PI: 0.21 to 0.31) per 10 000 adults. In years 6–10, the number of circumcisers needed fell to 513 (95% PI: 452 to 664). The estimated 5-year cost of rolling out MAMC in the public sector was $919 million (95% PI: 726 to 1 245). The cumulative net cost over the first 10 years was $672 million (95% PI: 437 to 1 021) and over 20 years there were net savings of $2.3 billion (95% PI: 1.4 to 3.4).

Conclusion

A rapid roll-out of MAMC in sub-Saharan Africa requires substantial funding and a high number of circumcisers for the first five years. These investments are justified by MAMC''s substantial health benefits and the savings accrued by averting future HIV infections. Lower ongoing costs and continued care savings suggest long-term sustainability.     

Pregnant women's access to PMTCT and ART services in South Africa and implications for universal antiretroviral treatment

Objectives

We describe pregnant womens'' access to PMTCT and HAART services and associated birth outcomes in South Africa.

Methods

Women recuperating in postnatal wards of a referral hospital participated in an evaluation during February–May 2010 during which their maternity records were examined to describe their access to VCT, CD4 Counts, dual ART or HAART during pregnancy.

Results

Of the 1609 women who participated in this evaluation, 39% (95%CI36.7–41.5%) tested HIV-positive during their pregnancy. Of the HIV-positive women 2.9% did not have a CD4 count done and an additional 31.3% did not receive their CD4 results. The majority (96.8%) of the HIV-positive women commenced dual ART at their first antenatal visit independent of their CD4 result. During February–May 2010, 48.0% of the women who had a CD4 result were eligible for HAART (CD4<200 cells/mm³) and 29.1% of these initiated HAART during pregnancy. Under the current South African PMTCT guidelines 71.1% (95%CI66.4–75.4%) of HIV positive pregnant women could be eligible for HAART (CD4<350 cells/mm³). There were significantly more preterm births among HIV-positive women (p = 0.01) and women who received HAART were no more at risk of preterm deliveries (AOR 0.73;95%CI0.39–1.36;p = 0.2) as compared to women who received dual ART. Nine (2.4%; 95%CI1.1–4.5%) HIV exposed infants were confirmed HIV infected at birth. The in-utero transmission rate was highest among women who required HAART but did not initiate treatment (8.5%) compared to 2.7% and 0.4% among women who received HAART and women who were not eligible for HAART and received PMTCT prophylaxis respectively.

Conclusion

In this urban South African community the antenatal HIV prevalence remains high (39%) and timeous access to CD4 results during pregnancy is limited. Under the current South African guidelines, and assuming that access to CD4 results has improved, more than 70% of HIV-positive pregnant women in this community would be requiring HAART.     

Scaling up the 2010 World Health Organization HIV Treatment Guidelines in resource-limited settings: a model-based analysis

Background

The new 2010 World Health Organization (WHO) HIV treatment guidelines recommend earlier antiretroviral therapy (ART) initiation (CD4<350 cells/µl instead of CD4<200 cells/µl), multiple sequential ART regimens, and replacement of first-line stavudine with tenofovir. This paper considers what to do first in resource-limited settings where immediate implementation of all of the WHO recommendations is not feasible.

Methods and Findings

We use a mathematical model and local input data to project clinical and economic outcomes in a South African HIV-infected cohort (mean age = 32.8 y, mean CD4 = 375/µl). For the reference strategy, we assume that all patients initiate stavudine-based ART with WHO stage III/IV disease and receive one line of ART (stavudine/WHO/one-line). We rank—in survival, cost-effectiveness, and equity terms—all 12 possible combinations of the following: (1) stavudine replacement with tenofovir, (2) ART initiation (by WHO stage, CD4<200 cells/µl, or CD4<350 cells/µl), and (3) one or two regimens, or lines, of available ART. Projected life expectancy for the reference strategy is 99.0 mo. Considering each of the guideline components separately, 5-y survival is maximized with ART initiation at CD4<350 cells/µl (stavudine/<350/µl/one-line, 87% survival) compared with stavudine/WHO/two-lines (66%) and tenofovir/WHO/one-line (66%). The greatest life expectancies are achieved via the following stepwise programmatic additions: stavudine/<350/µl/one-line (124.3 mo), stavudine/<350/µl/two-lines (177.6 mo), and tenofovir/<350/µl/two-lines (193.6 mo). Three program combinations are economically efficient: stavudine/<350/µl/one-line (cost-effectiveness ratio, US$610/years of life saved [YLS]), tenofovir/<350/µl/one-line (US$1,140/YLS), and tenofovir/<350/µl/two-lines (US$2,370/YLS).

Conclusions

In settings where immediate implementation of all of the new WHO treatment guidelines is not feasible, ART initiation at CD4<350 cells/µl provides the greatest short- and long-term survival advantage and is highly cost-effective. Please see later in the article for the Editors'' Summary     

Will Adoption of the 2010 WHO ART Guidelines for HIV-Infected TB Patients Increase the Demand for ART Services in India?

Background

In 2010, WHO expanded previously-recommended indications for anti-retroviral treatment to include all HIV-infected TB patients irrespective of CD4 count. India, however, still limits ART to those TB patients with CD4 counts <350/mm³ or with extrapulmonary TB manifestations. We sought to evaluate the additional number of patients that would be initiated on ART if India adopted the current 2010 WHO ART guidelines for HIV-infected TB patients.

Methods

We evaluated all TB patients recorded in treatment registers of the Revised National TB Control Programme in June 2010 in the high-HIV prevalence state of Karnataka, and cross-matched HIV-infected TB patients with ART programme records.

Results

Of 6182 TB patients registered, HIV status was ascertained for 5761(93%) and 710(12%) were HIV-infected. 146(21%) HIV-infected TB patients were on ART prior to TB diagnosis. Of the remaining 564, 497(88%) were assessed for ART eligibility; of these, 436(88%) were eligible for ART according to 2006 WHO ART guidelines. Altogether, 487(69%) HIV-infected TB patients received ART during TB treatment. About 80% started ART within 8 weeks of TB treatment and 95% received an efavirenz based regimen.

Conclusion

In Karnataka, India, about nine out of ten HIV-infected TB patients were eligible for ART according to 2006 WHO ART guidelines. The efficiency of HIV case finding, ART evaluation, and ART initiation was relatively high, with 78% of eligible HIV-infected patients actually initiated on ART, and 80% within 8 weeks of diagnosis. ART could be extended to all HIV-infected TB patients irrespective of CD4 count with relatively little additional burden on the national ART programme.     

Factors influencing retention in care after starting antiretroviral therapy in a rural South African programme

Introduction

The prognosis of patients with HIV in Africa has improved with the widespread use of antiretroviral therapy (ART) but these successes are threatened by low rates of long-term retention in care. There are limited data on predictors of retention in care, particularly from rural sites.

Methods

Prospective cohort analysis of outcome measures in adults from a rural HIV care programme in Madwaleni, Eastern Cape, South Africa. The ART programme operates from Madwaleni hospital and seven primary care feeder clinics with full integration between inpatient and outpatient services. Outreach workers conducted home visits for defaulters.

Results

1803 adults initiated ART from June 2005 to May 2009. At the end of the study period 82.4% were in active care or had transferred elsewhere, 11.1% had died and 6.5% were lost to follow-up (LTFU). Independent predictors associated with an increased risk of LTFU were CD4 nadir >200, initiating ART as an inpatient or while pregnant, and younger age, while being in care for >6 months before initiating ART was associated with a reduced risk. Independent factors associated with an increased risk of mortality were baseline CD4 count <50 and initiating ART as an inpatient, while being in care for >6 months before initiating ART and initiating ART while pregnant were associated with a reduced risk.

Conclusions

Serving a socioeconomically deprived rural population is not a barrier to successful ART delivery. Patients initiating ART while pregnant and inpatients may require additional counselling and support to reduce LTFU. Providing HIV care for patients not yet eligible for ART may be protective against being LTFU and dying after ART initiation.     

Long-term costs and health impact of continued global fund support for antiretroviral therapy

Background

By the end of 2011 Global Fund investments will be supporting 3.5 million people on antiretroviral therapy (ART) in 104 low- and middle-income countries. We estimated the cost and health impact of continuing treatment for these patients through 2020.

Methods and Findings

Survival on first-line and second-line ART regimens is estimated based on annual retention rates reported by national AIDS programs. Costs per patient-year were calculated from country-reported ARV procurement prices, and expenditures on laboratory tests, health care utilization and end-of-life care from in-depth costing studies. Of the 3.5 million ART patients in 2011, 2.3 million will still need treatment in 2020. The annual cost of maintaining ART falls from $1.9 billion in 2011 to $1.7 billion in 2020, as a result of a declining number of surviving patients partially offset by increasing costs as more patients migrate to second-line therapy. The Global Fund is expected to continue being a major contributor to meeting this financial need, alongside other international funders and domestic resources. Costs would be $150 million less in 2020 with an annual 5% decline in first-line ARV prices and $150–370 million less with a 5%–12% annual decline in second-line prices, but $200 million higher in 2020 with phase out of stavudine (d4T), or $200 million higher with increased migration to second-line regimens expected if all countries routinely adopted viral load monitoring. Deaths postponed by ART correspond to 830,000 life-years saved in 2011, increasing to around 2.3 million life-years every year between 2015 and 2020.

Conclusions

Annual patient-level direct costs of supporting a patient cohort remain fairly stable over 2011–2020, if current antiretroviral prices and delivery costs are maintained. Second-line antiretroviral prices are a major cost driver, underscoring the importance of investing in treatment quality to improve retention on first-line regimens.     

Effectiveness and cost effectiveness of expanding harm reduction and antiretroviral therapy in a mixed HIV epidemic: a modeling analysis for Ukraine

Background

Injection drug use (IDU) and heterosexual virus transmission both contribute to the growing mixed HIV epidemics in Eastern Europe and Central Asia. In Ukraine—chosen in this study as a representative country—IDU-related risk behaviors cause half of new infections, but few injection drug users (IDUs) receive methadone substitution therapy. Only 10% of eligible individuals receive antiretroviral therapy (ART). The appropriate resource allocation between these programs has not been studied. We estimated the effectiveness and cost-effectiveness of strategies for expanding methadone substitution therapy programs and ART in mixed HIV epidemics, using Ukraine as a case study.

Methods and Findings

We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs using opiates, and IDUs on methadone substitution therapy, stratified by HIV status, and populated it with data from the Ukraine. We considered interventions expanding methadone substitution therapy, increasing access to ART, or both. We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost-effectiveness. Without incremental interventions, HIV prevalence reached 67.2% (IDUs) and 0.88% (non-IDUs) after 20 years. Offering methadone substitution therapy to 25% of IDUs reduced prevalence most effectively (to 53.1% IDUs, 0.80% non-IDUs), and was most cost-effective, averting 4,700 infections and adding 76,000 QALYs compared with no intervention at US$530/QALY gained. Expanding both ART (80% coverage of those eligible for ART according to WHO criteria) and methadone substitution therapy (25% coverage) was the next most cost-effective strategy, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy and averting 8,300 infections versus no intervention. Expanding only ART (80% coverage) added 38,000 QALYs at US$2,240/QALY gained versus the methadone substitution therapy-only strategy, and averted 4,080 infections versus no intervention. Offering ART to 80% of non-IDUs eligible for treatment by WHO criteria, but only 10% of IDUs, averted only 1,800 infections versus no intervention and was not cost effective.

Conclusions

Methadone substitution therapy is a highly cost-effective option for the growing mixed HIV epidemic in Ukraine. A strategy that expands both methadone substitution therapy and ART to high levels is the most effective intervention, and is very cost effective by WHO criteria. When expanding ART, access to methadone substitution therapy provides additional benefit in infections averted. Our findings are potentially relevant to other settings with mixed HIV epidemics. Please see later in the article for the Editors'' Summary     

Economic impact of dengue illness and the cost-effectiveness of future vaccination programs in Singapore

Background

Dengue illness causes 50–100 million infections worldwide and threatens 2.5 billion people in the tropical and subtropical regions. Little is known about the disease burden and economic impact of dengue in higher resourced countries or the cost-effectiveness of potential dengue vaccines in such settings.

Methods and Findings

We estimate the direct and indirect costs of dengue from hospitalized and ambulatory cases in Singapore. We consider inter alia the impacts of dengue on the economy using the human-capital and the friction cost methods. Disease burden was estimated using disability-adjusted life years (DALYs) and the cost-effectiveness of a potential vaccine program was evaluated. The average economic impact of dengue illness in Singapore from 2000 to 2009 in constant 2010 US$ ranged between $0.85 billion and $1.15 billion, of which control costs constitute 42%–59%. Using empirically derived disability weights, we estimated an annual average disease burden of 9–14 DALYs per 100 000 habitants, making it comparable to diseases such as hepatitis B or syphilis. The proportion of symptomatic dengue cases detected by the national surveillance system was estimated to be low, and to decrease with age. Under population projections by the United Nations, the price per dose threshold for which vaccines stop being more cost-effective than the current vector control program ranged from $50 for mass vaccination requiring 3 doses and only conferring 10 years of immunity to $300 for vaccination requiring 2 doses and conferring lifetime immunity. The thresholds for these vaccine programs to not be cost-effective for Singapore were $100 and $500 per dose respectively.

Conclusions

Dengue illness presents a serious economic and disease burden in Singapore. Dengue vaccines are expected to be cost-effective if reasonably low prices are adopted and will help to reduce the economic and disease burden of dengue in Singapore substantially.     

Treatment interruption and variation in tablet taking behaviour result in viral failure: a case-control study from Cape Town, South Africa

Background

Understanding of the impact of non-structured treatment interruption (TI) and variation in tablet-taking on failure of first-line antiretroviral therapy (ART) is limited in a resource-poor setting.

Methods

A retrospective matched case-control analysis. Individuals failing ART were matched by time on ART with 4 controls. Viral load (VL) and CD4 count were completed 4-monthly. Adherence percentages, from tablet returns, were calculated 4-monthly (interval) and from ART start (cumulative). Variation between intervals and TI (>27 days off ART) were recorded. Conditional multivariate logistic regression analysis was performed to estimate the effect of cumulative adherence <90%, at least one episode of adherence variation >10% and TI on virological failure. Age, gender, baseline log VL and CD4 were included as possible confounders in the multivariate model.

Results

244 patients (44 cases, 200 controls) were included. Median age was 32 years (IQR28–37), baseline CD4 108 cells/mm3 (IQR56–151), VL 4.82 log (IQR4.48–5.23). 94% (96% controls, 86% failures) had cumulative adherence >90%. The odds of failure increased 3 times (aOR 3.01, 95%CI 0.81–11.21) in individuals with cumulative adherence <90%, 2.2 times (aOR 2.20, 95%CI 1.04–4.64) in individuals with at least one episode of fluctuating adherence of >10% and 4.01 times (aOR 4.01, 95%CI 1.45–11.10) in individuals with TIs. For individuals with TI and cumulative adherence >95%, the odds of failing were 5.65 (CI 1.40–22.85).

Conclusion

It is well known that poor cumulative adherence increases risk of virological failure, but less well understood that TI and variations in tablet-taking also play a key role, despite otherwise excellent adherence.     

Integrating prevention of mother-to-child HIV transmission programs to improve uptake: a systematic review

Background

We performed a systematic review to assess the effect of integrated perinatal prevention of mother-to-child transmission of HIV interventions compared to non- or partially integrated services on the uptake in low- and middle-income countries.

Methods

We searched for experimental, quasi-experimental and controlled observational studies in any language from 21 databases and grey literature sources.

Results

Out of 28 654 citations retrieved, five studies met our inclusion criteria. A cluster randomized controlled trial reported higher probability of nevirapine uptake at the labor wards implementing HIV testing and structured nevirapine adherence assessment (RRR 1.37, bootstrapped 95% CI, 1.04–1.77). A stepped wedge design study showed marked improvement in antiretroviral therapy (ART) enrolment (44.4% versus 25.3%, p<0.001) and initiation (32.9% versus 14.4%, p<0.001) in integrated care, but the median gestational age of ART initiation (27.1 versus 27.7 weeks, p = 0.4), ART duration (10.8 versus 10.0 weeks, p = 0.3) or 90 days ART retention (87.8% versus 91.3%, p = 0.3) did not differ significantly. A cohort study reported no significant difference either in the ART coverage (55% versus 48% versus 47%, p = 0.29) or eight weeks of ART duration before the delivery (50% versus 42% versus 52%; p = 0.96) between integrated, proximal and distal partially integrated care. Two before and after studies assessed the impact of integration on HIV testing uptake in antenatal care. The first study reported that significantly more women received information on PMTCT (92% versus 77%, p<0.001), were tested (76% versus 62%, p<0.001) and learned their HIV status (66% versus 55%, p<0.001) after integration. The second study also reported significant increase in HIV testing uptake after integration (98.8% versus 52.6%, p<0.001).

Conclusion

Limited, non-generalizable evidence supports the effectiveness of integrated PMTCT programs. More research measuring coverage and other relevant outcomes is urgently needed to inform the design of services delivering PMTCT programs.     

Taking ART to Scale: Determinants of the Cost and Cost-Effectiveness of Antiretroviral Therapy in 45 Clinical Sites in Zambia

Background

We estimated the unit costs and cost-effectiveness of a government ART program in 45 sites in Zambia supported by the Centre for Infectious Disease Research Zambia (CIDRZ).

Methods

We estimated per person-year costs at the facility level, and support costs incurred above the facility level and used multiple regression to estimate variation in these costs. To estimate ART effectiveness, we compared mortality in this Zambian population to that of a cohort of rural Ugandan HIV patients receiving co-trimoxazole (CTX) prophylaxis. We used micro-costing techniques to estimate incremental unit costs, and calculated cost-effectiveness ratios with a computer model which projected results to 10 years.

Results

The program cost $69.7 million for 125,436 person-years of ART, or $556 per ART-year. Compared to CTX prophylaxis alone, the program averted 33.3 deaths or 244.5 disability adjusted life-years (DALYs) per 100 person-years of ART. In the base-case analysis, the net cost per DALY averted was $833 compared to CTX alone. More than two-thirds of the variation in average incremental total and on-site cost per patient-year of treatment is explained by eight determinants, including the complexity of the patient-case load, the degree of adherence among the patients, and institutional characteristics including, experience, scale, scope, setting and sector.

Conclusions and Significance

The 45 sites exhibited substantial variation in unit costs and cost-effectiveness and are in the mid-range of cost-effectiveness when compared to other ART programs studied in southern Africa. Early treatment initiation, large scale, and hospital setting, are associated with statistically significantly lower costs, while others (rural location, private sector) are associated with shifting cost from on- to off-site. This study shows that ART programs can be significantly less costly or more cost-effective when they exploit economies of scale and scope, and initiate patients at higher CD4 counts.     

Validation of World Health Organisation HIV/AIDS clinical staging in predicting initiation of antiretroviral therapy and clinical predictors of low CD4 cell count in Uganda

Introduction

The WHO clinical guidelines for HIV/AIDS are widely used in resource limited settings to represent the gold standard of CD4 counts for antiviral therapy initiation. The utility of the WHO-defined stage 1 and 2 clinical factors used in WHO HIV/AIDS clinical staging in predicting low CD4 cell count has not been established in Uganda. Although the WHO staging has shown low sensitivity for predicting CD4<200cells/mm³, it has not been evaluated at for CD4 cut-offs of <250cells/mm³ or <350 cells/mm³.

Objective

To validate the World Health Organisation HIV/AIDS clinical staging in predicting initiation of antiretroviral therapy in a low-resource setting and to determine the clinical predictors of low CD4 cell count in Uganda.

Results

Data was collected on 395 participants from the Joint Clinical Research Centre, of whom 242 (61.3%) were classified as in stages 1 and 2 and 262 (68%) were females. Participants had a mean age of 36.8 years (SD 8.5). We found a significant inverse correlation between the CD4 lymphocyte count and WHO clinical stages. The sensitivity the WHO clinical staging at CD4 cell count of 250 cells/mm³ and 350cells/mm³ was 53.5% and 49.1% respectively. Angular cheilitis, papular pruritic eruptions and recurrent upper respiratory tract infections were found to be significant predictors of low CD4 cell count among participants in WHO stage 1 and 2.

Conclusion

The WHO HIV/AIDS clinical staging guidelines have a low sensitivity and about half of the participants in stages 1 and 2 would be eligible for ART initiation if they had been tested for CD4 count. Angular cheilitis and papular pruritic eruptions and recurrent upper respiratory tract infections may be used, in addition to the WHO staging, to improve sensitivity in the interim, as access to CD4 machines increases in Uganda.     

HIV Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential Impact of Antiretroviral Therapy on HIV Incidence in South Africa

Background

Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART.

Methods and Findings

Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results.

Conclusions

Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact. Please see later in the article for the Editors'' Summary     

CD4 dynamics over a 15 year-period among HIV controllers enrolled in the ANRS French observatory

Background

There are few large published studies of HIV controllers with long-term undetectable viral load (VL). We describe the characteristics and outcomes of 81 French HIV controllers.

Methods and Results

HIV controllers were defined as asymptomatic, antiretroviral-naïve persons infected ≥10 years previously, with HIV-RNA <400 copies/mL in >90% of plasma samples. All available CD4 and VL values were collected at enrolment. Mixed-effect linear models were used to analyze CD4 cell count slopes since diagnosis. HIV controllers represented 0.31% of all patients managed in French hospitals. Patients infected through intravenous drug use were overrepresented (31%) and homosexual men were underrepresented (26% of men) relative to the ANRS SEROCO cohort of subjects diagnosed during the same period. HIV controllers whose VL values were always below the detection limit of the assays were compared with those who had rare “blips” (<50% of VL values above the detection limit) or frequent blips (>50% of VL values above the detection limit). Estimated CD4 cell counts at HIV diagnosis were similar in the three groups. CD4 cell counts remained stable after HIV diagnosis in the “no blip” group, while they fell significantly in the two other groups (−0.26√CD4 and −0.28√CD4/mm³/year in the rare and frequent blip groups, respectively). No clinical, immunological or virological progression was observed in the no blip group, while 3 immunological and/or virological events and 4 cancers were observed in the blip subgroups.

Conclusions

Viral blips in HIV controllers are associated with a significant decline in CD4 T cells and may be associated with an increased risk of pathological events, possibly owing to chronic inflammation/immune activation.     

Comparison of HIV-, HBV-, HCV- and co-infection prevalence between Chinese and Burmese intravenous drug users of the China-Myanmar border region

Background

Co-infection with HIV and HCV and/or HBV is highly prevalent in intravenous drug users (IDUs). Because of the proximity to the “Golden Triangle”, HIV prevalence among the IDUs is very high in the China-Myanmar border region. However, there are few studies about co-infection with HIV and HCV and/or HBV, especially in the region that belongs to Myanmar.

Methods

721 IDUs, including 403 Chinese and 318 Burmese, were investigated for their HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) serological status. Statistical analysis was performed to evaluate the differences of the epidemic situation between the Chinese IDUs and the Burmese IDUs.

Results

Among the Chinese IDUs and the Burmese IDUs, HCV infection was the most prevalent (69.0% vs 48.1%, P<0.001), followed by HBV (51.6% vs 43.1%, P<0.05) and HIV (33.7% vs 27.0%, P>0.05). Besides, there were more HIV-HBV co-infected IDUs (20.1% vs 11.3%, P<0.005), and HIV-HCV co-infected IDUs (31.8% vs 23.9%, P<0.05) in China than in Myanmar, as well as HIV-HBV-HCV triple infection (19.1% vs 10.4%, P<0.005).

Conclusion

Co-infection with HIV and HCV and/or HBV is highly prevalent among the IDUs in the China-Myanmar border region. The HIV epidemic appears to be in a downward trend, compared with previous reports. However, all infections were more prevalent among the Chinese IDUs than among the Burmese.