Elizabeth M. Stringer

A Pilot Study of Food Supplementation to Improve Adherence to Antiretroviral Therapy Among Food-Insecure Adults in Lusaka, Zambia

Background:The provision of food supplementation to food-insecure patients initiating antiretroviral therapy (ART) may improve adherence to medications. Methods:A home-based adherence support program at 8 government clinics assessed patients for food insecurity. Four clinics provided food supplementation, and 4 acted as controls. The analysis compared adherence (assessed by medication possession ratio), CD4, and weight gain outcomes among food-insecure patients enrolled at the food clinics with those enrolled at the control clinics. Results:Between May 1, 2004, and March 31, 2005, 636 food- insecure adults were enrolled. Food supplementation was associated with better adherence to therapy. Two hundred fifty-eight of 366 (70%) patients in the food group achieved a medication possession ratio of 95% or greater versus 79 of 166 (48%) among controls (relative risk = 1.5; 95% confidence interval: 1.2 to 1.8). This finding was unchanged after adjustment for sex, age, baseline CD4 count, baseline World Health Organization stage, and baseline hemoglobin. We did not observe a significant effect of food supplementation on weight gain or CD4 cell response. Conclusions:This analysis suggests that providing food to food-insecure patients initiating ART is feasible and may improve adherence to medication. A large randomized study of the clinical benefits of food supplementation to ART patients is urgently needed to inform international policy.

Prevention of mother-to-child transmission of HIV in Africa: successes and challenges in scaling-up a nevirapine-based program in Lusaka, Zambia

Background: Nearly half of perinatal HIV infection is preventable with nevirapine (NVP), which has transformed the ability to confront this transmission route in resource‐limited settings. Methods: A NVP‐based perinatal HIV prevention program initiated in Lusaka, Zambia in November 2001. Results: The first 12 months cost US

Sex steroid hormones, hormonal contraception, and the immunobiology of human immunodeficiency virus-1 infection

221 000 and enabled 178 district health employees to be trained in voluntary counseling and testing: 17 263 pregnant women were counseled for HIV, 12 438 (72%) were tested, and 2924 (24%) were found to be infected with HIV. NVP has been taken by 1654 (57%) mothers and 1157 (40%) babies. It is estimated that at least 190 infants have been spared HIV infection (11 per 1000 counseled women or 65 per 1000 identified HIV‐infected women). Conclusions: Prevention of mother‐to‐child HIV transmission is feasible and cost effective in resource‐limited settings. In Lusaka, thousands of women have received voluntary counseling and testing and NVP therapy under the present scheme. Patient attrition and non‐adherence represented a major source of program inefficiency, which requires to be systematically addressed.

Effectiveness of a city-wide program to prevent mother-to-child HIV transmission in Lusaka, Zambia

Worldwide, an increasing number of women use oral or injectable hormonal contraceptives. However, inadequate information is available to aid women and health care professionals in weighing the potential risks of hormonal contraceptive use in individuals living with HIV-1 or at high risk of infection. Numerous epidemiological studies and challenge studies in a rhesus macaque model suggest that progesterone-based contraceptives increase the risk of HIV-1 infection in humans and simian immunodeficiency virus (SIV) infection in macaques, accelerate disease progression, and increase viral shedding in the genital tract. However, because several other studies in humans have not observed any effect of exogenously administered progesterone on HIV-1 acquisition and disease progression, the issue continues to be a topic of intense research and ongoing discussion. In contrast to progesterone, systemic or intravaginal treatment with estrogen efficiently protects female rhesus macaques against the transmission of SIV, likely by enhancing the natural protective properties of the lower genital tract mucosal tissue. Although the molecular and cellular mechanisms underlying the effect of sex steroid hormones on HIV-1 and SIV acquisition and disease progression are not well understood, progesterone and estrogen are known to regulate a number of immune mechanisms that may exert an effect on retroviral infection. This review summarizes current knowledge of the effects of various types of sex steroid hormones on immune processes involved in the biology of HIV-1 infection.

Monitoring effectiveness of programmes to prevent mother-to-child HIV transmission in lower-income countries

Objective:To determine the population effectiveness of a city-wide perinatal HIV prevention program. Design:An anonymous surveillance of newborn cord blood for HIV serology and nevirapine (NVP). Methods:All 10 public-sector delivery centers in Lusaka, Zambia participated. All mother–infant pairs delivering during the 12-week surveillance period at the participating centers and who received antenatal care at a public-sector facility in Lusaka were included in the study. The main outcome measure was population NVP coverage, defined as the proportion of HIV-infected women and HIV-exposed infants in the population that ingested NVP. Results:Of 8787 women in the surveillance population, 7204 (82%) had been offered antenatal HIV testing, of which 5149 (71%) had accepted, and of which 5129 (99%) had received a result. Overall, 2257 of 8787 (26%) were cord seropositive. Of the 1246 (55%) cord blood seropositive women who received an antenatal HIV test result, 1112 (89%) received a positive result; the other 134 comprise seroconverters and clerical errors. Only 751 of 1112 (68%) women who received a positive antenatal test result and a NVP tablet for ingestion at labor onset had NVP detected in the cord blood (i.e., maternal non-adherence rate was 32%). A total of 675 infants born to 751 adherent mothers (90%) received NVP before discharge. Thus, only 675 of 2257 (30%) seropositive mother–infant pairs in the surveillance population received both a maternal and infant dose of NVP. Conclusions:Successful perinatal HIV prevention requires each mother–infant pair to negotiate a cascade of events that begins with offering HIV testing and continues through adherence to the prescribed regimen. This novel surveillance demonstrates that failures occur at each step, resulting in reduced coverage and diminished program effectiveness.

Antiretroviral Therapies in Women after Single-Dose Nevirapine Exposure

Ambitious goals for paediatric AIDS control have been set by various international bodies, including a 50% reduction in new paediatric infections by 2010. While these goals are clearly appropriate in their scope, the lack of clarity and consensus around how to monitor the effectiveness of programmes to prevent mother-to-child HIV transmission (PMTCT) makes it difficult for policy-makers to mount a coordinated response. In this paper, we develop the case for using population HIV-free child survival as a gold standard metric to measure the effectiveness of PMTCT programmes, and go on to consider multiple study designs and source populations. Finally, we propose a novel community survey-based approach that could be implemented widely throughout the developing world with minor modifications to ongoing Demographic and Health Surveys.

Single-dose tenofovir and emtricitabine for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: an open-label randomised trial

BACKGROUND Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus. METHODS In seven African countries, women infected with HIV-1 whose CD4+ T-cell counts were below 200 per cubic millimeter and who either had or had not taken single-dose nevirapine at least 6 months before enrollment were randomly assigned to receive antiretroviral therapy with tenofovir–emtricitabine plus nevirapine or tenofovir-emtricitabine plus lopinavir boosted by a low dose of ritonavir. The primary end point was the time to confirmed virologic failure or death. RESULTS A total of 241 women who had been exposed to single-dose nevirapine began the study treatments (121 received nevirapine and 120 received ritonavir-boosted lopinavir). Significantly more women in the nevirapine group reached the primary end point than in the ritonavir-boosted lopinavir group (26% vs. 8%) (adjusted P=0.001). Virologic failure occurred in 37 (28 in the nevirapine group and 9 in the ritonavir-boosted lopinavir group), and 5 died without prior virologic failure (4 in the nevirapine group and 1 in the ritonavir-boosted lopinavir group). The group differences appeared to decrease as the interval between single-dose nevirapine exposure and the start of antiretroviral therapy increased. Retrospective bulk sequencing of baseline plasma samples showed nevirapine resistance in 33 of 239 women tested (14%). Among 500 women without prior exposure to single-dose nevirapine, 34 of 249 in the nevirapine group (14%) and 36 of 251 in the ritonavir-boosted lopinavir group (14%) had virologic failure or died. CONCLUSIONS In women with prior exposure to peripartum single-dose nevirapine (but not in those without prior exposure), ritonavir-boosted lopinavir plus tenofovir–emtricitabine was superior to nevirapine plus tenofovir–emtricitabine for initial antiretroviral therapy. (Funded by the National Institute of Allergy and Infectious Diseases and the National Research Center; ClinicalTrials.gov number, NCT00089505.).

Baseline renal insufficiency and risk of death among HIV-infected adults on antiretroviral therapy in Lusaka, Zambia

BACKGROUND Intrapartum and neonatal single-dose nevirapine are essential components of perinatal HIV prevention in resource-constrained settings, but can induce resistance to other non-nucleoside reverse transcriptase inhibitor drugs. We aimed to investigate whether this complication would be reduced with a single peripartum intervention of tenofovir and emtricitabine. METHODS We randomly assigned 400 HIV-infected pregnant women who sought care at two public-sector primary health facilities in Lusaka, Zambia. One was excluded, 200 were assigned to receive a single oral dose of 300 mg tenofovir disoproxil fumarate with 200 mg emtricitabine under direct observation, and 199 to receive no study drug. Short-course zidovudine and intrapartum nevirapine were offered to all HIV-infected women, according to the local standard of care. Women who met national criteria for antiretroviral therapy were referred for care and not enrolled. Our primary study outcome was resistance to non-nucleoside reverse transcriptase inhibitors at 6 weeks after delivery. We used standard population sequencing to determine HIV genotypes. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00204308. FINDINGS Of the 200 women who were randomly assigned to the intervention, 14 were lost to follow-up or withdrew from the study, two did not take study drug according to protocol, and one specimen was lost; 23 of 199 controls were lost to follow-up or withdrew from the study, and three specimens were lost. Women given the intervention were 53% less likely than controls to have a mutation that conferred resistance to non-nucleoside reverse transcriptase inhibitors at 6 weeks after delivery (20/173 [12%] vs 41/166 [25%]; risk ratio [RR] 0.47, 95% CI 0.29-0.76). We noted postpartum anaemia, the most common serious adverse event in mothers, in four women in each group. 20 of 198 (10%) infants in the intervention group and 23 of 199 (12%) controls had a serious adverse event, mostly due to septicaemia (n=22) or pneumonia (n=8); these events did not differ between groups, and none were judged to be caused by the study intervention. INTERPRETATION A single dose of tenofovir and emtricitabine at delivery reduced resistance to non-nucleoside reverse transcriptase inhibitors at 6 weeks after delivery by half; therefore this treatment should be considered as an adjuvant to intrapartum nevirapine.

Evaluation of a new testing policy for human immunodeficiency virus to improve screening rates

Objective:To examine the association between baseline renal insufficiency and mortality among adults initiating antiretroviral therapy (ART) in an urban African setting. Design:Open cohort evaluation. Methods:We examined mortality according to baseline renal function among adults initiating ART in Lusaka, Zambia. Renal function was assessed by the Cockcroft–Gault method, the Modification of Diet in Renal Disease equation, and serum creatinine. Results:From April 2004 to September 2007, 25 779 individuals started ART with an available creatinine measurement at baseline. When creatinine clearance was calculated by the Cockcroft–Gault method, 8456 (33.5%) had renal insufficiency: 73.5% were mild (60–89 ml/min), 23.4% moderate (30–59 ml/min), and 3.1% severe (<30 ml/min). Risk for mortality at or before 90 days was elevated for those with mildly [adjusted hazard ratio (AHR) = 1.7; 95% confidence interval (95% CI) = 1.5–1.9], moderately (AHR = 2.3; 95% CI = 2.0–2.7), and severely (AHR = 4.3; 95% CI = 3.1–5.5) reduced creatinine clearance. Mild (AHR = 1.4; 95% CI = 1.2–1.6), moderate (AHR = 1.9; 95% CI = 1.5–2.3), and severe (AHR = 3.6; 95% CI = 2.4–5.5) insufficiency were also associated with increased mortality after 90 days, when compared with those with normal renal function. Trends were similar when renal function was estimated with Modification of Diet in Renal Disease or serum creatinine. Conclusion:Renal insufficiency at time of ART initiation was prevalent and associated with increased mortality risk among adults in this population. These results have particular relevance for settings like Zambia, where tenofovir – a drug with known nephrotoxicity – has been adopted as part of first-line therapy. This emphasizes the need for resource-appropriate screening algorithms for renal disease, both as part of ART eligibility and pretreatment assessment.

Antiretroviral therapy in antenatal care to increase treatment initiation in HIV-infected pregnant women: a stepped-wedge evaluation

OBJECTIVE To assess the effect of a change in human immunodeficiency virus (HIV) testing policy on HIV testing rates in an urban maternity clinic population. METHODS Since 1995, our institution has provided pretest counseling and voluntary HIV testing to all pregnant women. After the 1999 Institute of Medicine recommendation of HIV testing with patient notification as a routine component of prenatal care, we conducted a prospective study to determine whether this policy would increase our HIV screening rates. The intervention incorporated HIV testing into the routine battery of tests drawn at antenatal care. Not to be tested required active refusal. The intervention group was comprised of all women receiving an initial antenatal visit in one of our eight maternity clinics between August 1, 1999, and July 30, 2000. The control group was comprised of all women presenting for prenatal care in the same clinics during the year before the intervention. RESULTS The 3415 women in the intervention group and 3778 controls were similar with respect to most demographic and risk factors. After the intervention, HIV testing increased from 75% to 88% (P < .001). Among all women in both years of the study, women who were in the intervention group, less than 20 years of age, or who had a history of substance abuse, were more likely not to refuse testing. CONCLUSION After implementation of a policy of routine HIV testing with active patient refusal, HIV testing rates increased among pregnant women in our large, urban obstetric clinic population.