The penile microbiota of Black South African men: relationship with human papillomavirus and HIV infection.

BACKGROUND: To date, the microbiota of the human penis has been studied mostly in connection with circumcision, HIV risk and female partner bacterial vaginosis (BV). These studies have shown that male circumcision reduces penile anaerobic bacteria, that greater abundance of penile anaerobic bacteria is correlated with increased cytokine levels and greater risk of HIV infection, and that the penile microbiota is an important harbour for BV-associated bacteria. While circumcision has been shown to significantly reduce the risk of acquiring human papillomavirus (HPV) infection, the relationship of the penile microbiota with HPV is still unknown. In this study, we examined the penile microbiota of HPV-infected men as well as the impact of HIV status. RESULTS: The penile skin microbiota of 238 men from Cape Town (South Africa) were profiled using Illumina sequencing of the V3-V4 hypervariable regions of the 16S rRNA gene. Corynebacterium and Prevotella were found to be the most abundant genera. Six distinct community state types (CSTs) were identified. CST-1, dominated by Corynebacterium, corresponded to less infections with high-risk HPV (HR-HPV) relative to CSTs 2-6. Men in CST-5 had greater relative abundances of Prevotella, Clostridiales, and Porphyromonas and a lower relative abundance of Corynebacterium. Moreover, they were significantly more likely to have HPV or HR-HPV infections than men in CST-1. Using a machine learning approach, we identified greater relative abundances of the anaerobic BV-associated bacteria (Prevotella, Peptinophilus, and Dialister) and lower relative abundance of Corynebacterium in HR-HPV-infected men compared to HR-HPV-uninfected men. No association was observed between HIV and CST, although the penile microbiota of HIV-infected men had greater relative abundances of Staphylococcus compared to HIV-uninfected men. CONCLUSIONS: We found significant differences in the penile microbiota composition of men with and without HPV and HIV infections. HIV and HR-HPV infections were strongly associated with greater relative abundances of Staphylococcus and BV-associated bacterial taxa (notably Prevotella, Peptinophilus and Dialister), respectively. It is possible that these taxa could increase susceptibility to HIV and HR-HPV acquisition, in addition to creating conditions in which infections persist. Further longitudinal studies are required to establish causal relationships and to determine the extent of the effect.

Maternal Decision-Making and Uptake of Health Services for the Prevention of Mother-to-Child HIV Transmission: A Secondary Analysis.

Objectives We investigated whether a woman's role in household decision-making was associated with receipt of services to prevent mother-to-child HIV transmission (PMTCT). Methods We conducted a secondary analysis of the PEARL study, an evaluation of PMTCT effectiveness in Cameroon, Cote d'Ivoire, South Africa, and Zambia. Our exposure of interest was the women's role (active vs. not active) in decision-making about her healthcare, large household purchases, children's schooling, and children's healthcare (i.e., four domains). Our primary outcomes were self-reported engagement at three steps in PMTCT: maternal antiretroviral use, infant antiretroviral prophylaxis, and infant HIV testing. Associations found to be significant in univariable logistic regression were included in separate multivariable models. Results From 2008 to 2009, 613 HIV-infected women were surveyed and provided information about their decision-making roles. Of these, 272 (44.4%) women reported antiretroviral use; 281 (45.9%) reported infant antiretroviral prophylaxis; and 194 (31.7%) reported infant HIV testing. Women who reported an active role were more likely to utilize infant HIV testing services, across all four measured domains of decision-making (adjusted odds ratios [AORs] 2.00-2.89 all p < .05). However, associations between decision-making and antiretroviral use-for both mother and infant-were generally not significant. An exception was active decision-making in a woman's own healthcare and reported maternal antiretroviral use (AOR 1.69, p < 0.05). Conclusions for Practice Associations between decision-making and PMTCT engagement were inconsistent and may be related to specific characteristics of individual health-seeking behaviors. Interventions seeking to improve PMTCT uptake should consider the type of health-seeking behavior to better optimize health services.

CCR5 expression, haplotype and immune activation in protection from infection in HIV-exposed uninfected individuals in HIV-serodiscordant relationships.

Several host factors have been implicated in resistance to HIV infection in individuals who remain HIV-seronegative despite exposure. In a cohort of HIV-serodiscordant heterosexual couples, we investigated interactions between systemic inflammation and T-cell activation in resistance to HIV infection. Males and females in stable long-term relationships with either HIV-infected or uninfected partners were recruited, blood T-cell activation (CD38, HLA-DR, CCR5 and Ki67) and plasma cytokine concentrations were evaluated. The HIV-negative exposed individuals had significantly lower frequencies of CCR5+ CD4+ and CD8+ T cells than unexposed individuals. Mean fluorescence intensity of CCR5 expression on CD4+ T cells was significantly lower in HIV-negative exposed than unexposed individuals. Protective CCR5 haplotypes (HHA/HHF*2, HHF*2/HHF*2, HHC/HHF*2, HHA/HHA, HHA/HHC and HHA/HHD) tended to be over-represented in exposed compared with unexposed individuals (38% versus 28%, P = 0·58) whereas deleterious genotypes (HHC/HHD, HHC/HHE, HHD/HHE, HHD/HHD and HHE/HHE) were under-represented (26% versus 44%; P = 0·16). Plasma concentrations of interleukin-2 (P = 0·02), interferon-γ (P = 0·05) and granulocyte-macrophage colony-stimulating factor (P = 0·006) were lower in exposed compared with unexposed individuals. Activation marker expression and systemic cytokine concentrations were not influenced by gender. We conclude that the dominant signature of resistance to HIV infection in this cohort of exposed but uninfected individuals was lower T-cell CCR5 expression and plasma cytokine concentrations.

Linking mortuary data improves vital statistics on cause of death of children under five years in the Western Cape Province of South Africa.

OBJECTIVES: Reducing child mortality requires good information on its causes. Whilst South African vital registration data have improved, the quality of cause-of-death data remains inadequate. To improve this, data from death certificates were linked with information from forensic mortuaries in Western Cape Province. METHODS: A local mortality surveillance system was established in 2007 by the Western Cape Health Department to improve data quality. Cause-of-death data were captured from copies of death notification forms collected at Department of Home Affairs Offices. Using unique identifiers, additional forensic mortuary data were linked with mortality surveillance system records. Causes of death were coded to the ICD-10 classification. Causes of death in children under five were compared with those from vital registration data for 2011. RESULTS: Cause-of-death data were markedly improved with additional data from forensic mortuaries. The proportion of ill-defined causes was halved (25-12%), and leading cause rankings changed. Lower respiratory tract infections moved above prematurity to rank first, accounting for 20.8% of deaths and peaking in infants aged 1-3 months. Only 11% of deaths from lower respiratory tract infections occurred in hospital, resulting in 86% being certified in forensic mortuaries. Road traffic deaths increased from 1.1-3.1% (27-75) and homicides from 3 to 28. CONCLUSIONS: The quality and usefulness of cause-of-death information for children in the WC was enhanced by linking mortuary and vital registration data. Given the death profile, interventions are required to prevent and manage LRTI, diarrhoea and injuries and to reduce neonatal deaths.

Human papillomavirus prevalence in South African women and men according to age and human immunodeficiency virus status.

BACKGROUND: Both cervical cancer and human immunodeficiency virus (HIV) are major public health problems in Sub-Saharan Africa. The objectives of the study were to investigate human papillomavirus (HPV) prevalence according to age, HIV status and gender. METHODS: Participants were 208 HIV-negative women, 278 HIV-positive women, 325 HIV-negative men and 161 HIV-positive men between the ages of 18-66 years. HPV types were determined in cervical and penile cells by Roche Linear Array HPV genotyping assay. RESULTS: HPV prevalence was 36.7 % (76/207; 95 % confidence intervals (CI): 30.4-43.4 %) in HIV-negative women, with the highest prevalence of 61.0 % (25/41; 95 % CI: 45.7-74.4 %) in women aged 18-25 years. HPV prevalence was 74.0 % (205/277; 95 % CI: 68.5-78.8 %) in HIV-positive women, with the highest prevalence of 86.4 % (38/44; 95 % CI: 72.9-94.0 %) in women aged 18-25 years. HPV prevalence was found to decrease with increasing age in HIV-negative women (P = 0.0007), but not in HIV-positive women (P = 0.898). HPV prevalence was 50.8 % (159/313; 95 % CI: 45.3-56.3 %) in HIV-negative men, with the highest prevalence of 77.0 % (27/35; 95 % CI: 60.7-88.2 %) in men aged 18-25 years. HPV prevalence was 76.6 % (121/158; 95 % CI: 69.2-82.9 %) in HIV-positive men, with the highest prevalence of 87.5 % (7/8; 95 % CI: 50.8-99.9 %) in men 18-25 years of age. HPV prevalence was found to decrease with increasing age in HIV-negative men (P = 0.004), but not in HIV-positive men (P = 0.385). HIV-positive women had a significantly higher prevalence of one or more HPV type(s) in the bivalent (HPV-16/18: 20 % 55/277, 9 % 12/207; P <0.001), quadrivalent (HPV-6/11/16/18: 26 % 71/277, 12 % 24/207; P = 0.001) and nonavalent vaccine (HPV-6/11/16/18/31/33/52/56/58: 65 % 181/277, 24 % 50/207; P <0.001) compared to HIV-negative women. Similar observation were observed in men for bivalent (20 % 32/158, 10 % 30/313; P = 0.001), quadrivalent (35 % 56/158, 13 % 41/313; P <0.001) and nonavalent vaccine (75 % 119/158, 28 % 87/313; P <0.001). CONCLUSIONS: This study demonstrated high HPV prevalence among HIV-positive women and men in all age groups. The high prevalence of HPV types found in bivalent, quadrivalent and nonavalent vaccines in South African HIV-positive and HIV-negative women and men demonstrate that this population will greatly benefit from current HPV vaccines.

Distinct cytokine patterns in semen influence local HIV shedding and HIV target cell activation.

BACKGROUND: Semen is the main vector for human immunodeficiency virus (HIV) transmission from men to women. We investigated the influence of cytokines in semen on local HIV burden and activated T cells. METHODS: Blood and semen were collected from 42 HIV-negative and 38 HIV-positive men. Concentrations of 20 cytokines were measured by Luminex, and frequencies of activated T cells were measured by flow cytometry. RESULTS: Semen contained higher concentrations of proinflammatory (monocyte chemotactic protein-1, interleukin [IL]-8, IL-6, Fractalkine, macrophage inflammatory protein (MIP)-1ß, granulocyte macrophage colony-stimulating factor) and adaptive cytokines (IL-7 and IL-15) and higher frequencies of activated T cells compared to blood. Plasma IL-2, eotaxin, MIP-1ß, and IL-15 and semen eotaxin and granulocyte colony-stimulating factor (G-CSF) concentrations were associated with T-cell activation. Cytokines in semen were highly coregulated in HIV-negative men; however, this network was disrupted during HIV infection. Several cytokines in semen correlated with HIV shedding (G-CSF, tumor necrosis factor-alpha [TNF-α], interferon-gamma [IFN-γ], IL-10). CONCLUSION: Higher levels of inflammation and T-cell activation were observed in semen compared with blood. Seminal G-CSF, which influences neutrophil survival, T-cell function, and dendritic cell activation, was associated with T-cell activation and HIV shedding and may be an important target for reducing HIV shedding or risk.

Increased alpha-9 human papillomavirus species viral load in human immunodeficiency virus positive women.

BACKGROUND: Persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR-HPV viral load are associated with the development of cancer. This study investigated the effect of human immunodeficiency virus (HIV) co-infection, HIV viral load and CD4 count on the HR-HPV viral load; and also investigated the predictors of cervical abnormalities. METHODS: Participants were 292 HIV-negative and 258 HIV-positive women. HR-HPV viral loads in cervical cells were determined by the real-time polymerase chain reaction. RESULTS: HIV-positive women had a significantly higher viral load for combined alpha-9 HPV species compared to HIV-negative women (median 3.9 copies per cell compared to 0.63 copies per cell, P = 0.022). This was not observed for individual HPV types. HIV-positive women with CD4 counts >350/µl had significantly lower viral loads for alpha-7 HPV species (median 0.12 copies per cell) than HIV-positive women with CD4 ≤350/µl (median 1.52 copies per cell, P = 0.008), but low CD4 count was not significantly associated with increased viral load for other HPV species. High viral loads for alpha-6, alpha-7 and alpha-9 HPV species were significant predictors of abnormal cytology in women. CONCLUSION: HIV co-infection significantly increased the combined alpha-9 HPV viral load in women but not viral loads for individual HPV types. High HR-HPV viral load was associated with cervical abnormal cytology.

Measuring coverage in MNCH: population HIV-free survival among children under two years of age in four African countries.

BACKGROUND: Population-based evaluations of programs for prevention of mother-to-child HIV transmission (PMTCT) are scarce. We measured PMTCT service coverage, regimen use, and HIV-free survival among children ≤24 mo of age in Cameroon, Côte D'Ivoire, South Africa, and Zambia. METHODS AND FINDINGS: We randomly sampled households in 26 communities and offered participation if a child had been born to a woman living there during the prior 24 mo. We tested consenting mothers with rapid HIV antibody tests and tested the children of seropositive mothers with HIV DNA PCR or rapid antibody tests. Our primary outcome was 24-mo HIV-free survival, estimated with survival analysis. In an individual-level analysis, we evaluated the effectiveness of various PMTCT regimens. In a community-level analysis, we evaluated the relationship between HIV-free survival and community PMTCT coverage (the proportion of HIV-exposed infants in each community that received any PMTCT intervention during gestation or breastfeeding). We also compared our community coverage results to those of a contemporaneous study conducted in the facilities serving each sampled community. Of 7,985 surveyed children under 2 y of age, 1,014 (12.7%) were HIV-exposed. Of these, 110 (10.9%) were HIV-infected, 851 (83.9%) were HIV-uninfected, and 53 (5.2%) were dead. HIV-free survival at 24 mo of age among all HIV-exposed children was 79.7% (95% CI: 76.4, 82.6) overall, with the following country-level estimates: Cameroon (72.6%; 95% CI: 62.3, 80.5), South Africa (77.7%; 95% CI: 72.5, 82.1), Zambia (83.1%; 95% CI: 78.4, 86.8), and Côte D'Ivoire (84.4%; 95% CI: 70.0, 92.2). In adjusted analyses, the risk of death or HIV infection was non-significantly lower in children whose mothers received a more complex regimen of either two or three antiretroviral drugs compared to those receiving no prophylaxis (adjusted hazard ratio: 0.60; 95% CI: 0.34, 1.06). Risk of death was not different for children whose mothers received a more complex regimen compared to those given single-dose nevirapine (adjusted hazard ratio: 0.88; 95% CI: 0.45, 1.72). Community PMTCT coverage was highest in Cameroon, where 75 of 114 HIV-exposed infants met criteria for coverage (66%; 95% CI: 56, 74), followed by Zambia (219 of 444, 49%; 95% CI: 45, 54), then South Africa (152 of 365, 42%; 95% CI: 37, 47), and then Côte D'Ivoire (3 of 53, 5.7%; 95% CI: 1.2, 16). In a cluster-level analysis, community PMTCT coverage was highly correlated with facility PMTCT coverage (Pearson's r = 0.85), and moderately correlated with 24-mo HIV-free survival (Pearson's r = 0.29). In 14 of 16 instances where both the facility and community samples were large enough for comparison, the facility-based coverage measure exceeded that observed in the community. CONCLUSIONS: HIV-free survival can be estimated with community surveys and should be incorporated into ongoing country monitoring. Facility-based coverage measures correlate with those derived from community sampling, but may overestimate population coverage. The more complex regimens recommended by the World Health Organization seem to have measurable public health benefit at the population level, but power was limited and additional field validation is needed.

Impact of human immunodeficiency virus on the natural history of human papillomavirus genital infection in South African men and women.

BACKGROUND: This study investigated genital human papillomavirus (HPV) incidence and clearance in 278 human immunodeficiency virus (HIV)-seropositive (HIV-positive) women, 208 HIV-negative women, 161 HIV-positive men, and 325 HIV-negative men, followed at 6-month intervals for up to 24 months. METHODS: HPV types were determined by the Roche Reverse Linear Array HPV genotyping assay. RESULTS: The rate of new HPV detection at the cervix and penis were 33.83 events/1000 person-months (95% confidence interval [CI], 26.39-43.46) and 55.68 events/1000 person-months (95% CI, 43.59-69.19), respectively. HIV infection was associated with increased risk of new HPV detection in women (relative risk [RR], 2.98; 95% CI, 2.07-4.29) and men (RR, 2.00; 95% CI, 1.49-2.69). The risk of new HPV detection increased in women (RR, 5.25; 95% CI, 3.52-7.81) and men (RR, 8.71; 95% CI, 6.19-12.24) when the sexual partner was infected with the same HPV type. The rate of clearing any HPV infection was 95.1 events/1000 person-months (95% CI, 83.3-108.1) in men and 66.9 events/1000 person-months (95% CI, 57.0-78.5) in women. HIV infection reduced the rate of HPV clearance in women (RR, 0.46; 95% CI, .34-.62) and men (RR, 0.71; 95% CI, .55-.93). CONCLUSIONS: HIV infection increases the risk of new HPV detection and decreases the rate of HPV clearance in both women and men.

The role of sexually transmitted infections in the evolution of the South African HIV epidemic.

OBJECTIVES: To assess the extent to which sexually transmitted infections (STIs) have contributed to the spread of HIV in South Africa and to estimate the extent to which improvements in STI treatment have reduced HIV incidence. METHODS: A mathematical model was used to simulate interactions between HIV and six other STIs (genital herpes, syphilis, chancroid, gonorrhoea, chlamydial infection and trichomoniasis) as well as bacterial vaginosis and vaginal candidiasis. The effects of STIs on HIV transmission probabilities were assumed to be consistent with meta-analytic reviews of observational studies, and the model was fitted to South African HIV prevalence data. RESULTS: The proportion of new HIV infections in adults that were attributable to curable STIs reduced from 39% (uncertainty range: 24-50%) in 1990 to 14% (8-18%) in 2010, while the proportion of new infections attributable to genital herpes increased. Syndromic management programmes are estimated to have reduced adult HIV incidence by 6.6% (3.3-10.3%) between 1994 and 2004, by which time syndromic management coverage was 52%. Had syndromic management been introduced in 1986, with immediate achievement of 100% coverage and a doubling of the rate of health seeking, HIV incidence would have reduced by 64% (36-82%) over the next decade, but had the same intervention been delayed until 2004, HIV incidence would have reduced by only 5.5% (2.8-9.0%). CONCLUSIONS: Sexually transmitted infections have contributed significantly to the spread of HIV in South Africa, but STI control efforts have had limited impact on HIV incidence because of their late introduction and suboptimal coverage.

High yield of culture-based diagnosis in a TB-endemic setting.

BACKGROUND: In most of the world, microbiologic diagnosis of tuberculosis (TB) is limited to microscopy. Recent guidelines recommend culture-based diagnosis where feasible. METHODS: In order to evaluate the relative and absolute incremental diagnostic yield of culture-based diagnosis in a high-incidence community in Cape Town, South Africa, subjects evaluated for suspected TB had their samples processed for microscopy and culture over a 21 month period. RESULTS: For 2537 suspect episodes with 2 smears and 2 cultures done, 20.0% (508) had at least one positive smear and 29.9% (760) had at least one positive culture. One culture yielded 1.8 times more cases as 1 smear (relative yield), or an increase of 12.0% (absolute yield). Based on the latter value, the number of cultures needed to diagnose (NND) one extra case of TB was 8, compared to 19 if second specimens were submitted for microscopy. CONCLUSION: In a high-burden setting, the introduction of culture can markedly increase TB diagnosis over microscopy. The concept of number needed to diagnose can help in comparing incremental yield of diagnosis methods. Although new promising diagnostic molecular methods are being implemented, TB culture is still the gold standard.

Immune activation in the female genital tract during HIV infection predicts mucosal CD4 depletion and HIV shedding.

Plasma viral load predicts genital tract human immunodeficiency virus (HIV) shedding in HIV-infected women. We investigated whether local mucosal T-cell activation (HLA-DR, CD38, CCR5, and Ki67) contributed to HIV shedding in the genital tracts of HIV-infected women. We showed that cervical cytobrush-derived T cells expressed higher frequencies of T-cell activation markers (CD38+ and HLA-DR+) than blood-derived T cells. Expression was significantly higher in HIV-infected women than in uninfected women. We found that the frequency of activated proliferating cervical T cells (Ki67+; Ki67+CCR5+) broadly predicted HIV shedding in the genital tract in HIV-infected women, independently of plasma viral loads. Furthermore, activated cervical T cells (HLA-DR+CD38+ and HLA-DR+CCR5+) and local HIV shedding were independently associated with CD4 depletion in the genital tract. These data suggest that the presence of high frequencies of activated T cells in the female genital mucosa during HIV infection facilitates both local HIV shedding and CD4 T-cell depletion.

Alloimmunity to Class 2 Human Leucocyte Antigens May Reduce HIV-1 Acquisition - A Nested Case-Control Study in HIV-1 Serodiscordant Couples.

Enveloped viruses, including the Human Immunodeficiency Virus-1 (HIV), incorporate host proteins such as human leucocyte antigens (HLA) into their envelope. Pre-existing antibodies against HLA, termed HLA antibodies, may bind to these surface proteins and reduce viral infectivity. Related evidence includes macaque studies which suggest that xenoimmunization with HLA antigens may protect against simian immunodeficiency virus infection. Since HIV gp120 shows homology with class 2 HLA, including shared affinity for binding to CD4, class 2 HLA antibodies may influence HIV acquisition via binding to gp120 on the viral envelope. We conducted a nested case-control study on HIV serodiscordant couples, comparing the frequency of HLA antibodies among highly exposed persistently seronegative controls with those who went on to acquire HIV (HIV-seroconverters). We first performed low resolution HLA typing on 143 individuals who were HIV-infected at enrollment (index partners) and their corresponding sexual partners (115 highly exposed persistently seronegative individuals and 28 HIV-seroconverters). We then measured HLA class 1 and 2 antibodies in the highly exposed persistently seronegative individuals and HIV-seroconverters at early and late timepoints. We analyzed whether such antibodies were directed at HLA specificities of their HIV-infected index partners, and whether autoantibodies or complement-fixing class 2 HLA antibodies were present. Seventy-nine percent of highly exposed persistently seronegative individuals had HLA antibodies; 56% against class 1 and 50% against class 2 alleles. Half of the group of highly exposed persistently seronegative individuals, prior to seroconversion, expressed class 2 HLA antibodies, compared with only 29% of controls (p=0.05). HIV infection was a sensitizing event leading to de novo development of antibodies against HLA-A and HLA-B loci, but not against class 2 loci. HLA autoantibodies were present in 27% of highly exposed persistently seronegative individuals. Complement-fixing class 2 HLA antibodies did not differ significantly between highly exposed persistently seronegative individuals and seroconverters. In multivariable regression, presence of class 2 HLA antibodies at early timepoints was associated with reduced odds of HIV acquisition (odds ratio 0.330, confidence interval 0.112-0.976, p=0.045). These epidemiological data suggest that pre-existing class 2 HLA antibodies were associated with reduced odds of HIV acquisition.

Daily acyclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial.

BACKGROUND: Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of acyclovir on HIV-1 progression. METHODS: In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to acyclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per mL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of acyclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per microL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per microL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519. FINDINGS: At enrollment, the median CD4 cell count was 462 cells per microL and median HIV-1 plasma RNA was 4.1 log(10) copies per microL. Acyclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned acyclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% CI 0.71-0.98, p=0.03). In those with CD4 counts >or=350 cells per microL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per microL by 19% (0.81, 0.71-0.93, p=0.002) INTERPRETATION: The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration. FUNDING: Bill & Melinda Gates Foundation.

Using an adaptive, codesign approach to strengthen clinic-level immunisation services in Khayelitsha, Western Cape Province, South Africa.

INTRODUCTION: Optimal immunisation programme service delivery and childhood vaccine coverage remains an ongoing challenge in South Africa. Previous health systems approaches have made recommendations on how to address identified barriers but detailed local implementation studies are lacking. This study aimed to improve immunisation service delivery in children under 24 months in Khayelitsha, Western Cape Province using an adaptive, co-design approach to assess and improve childhood immunisation service delivery at the clinic level. METHODS: A rapid, adaptive approach to identification of barriers and assessment of current childhood immunisation service delivery was developed with three clinics in Khayelitsha, Western Cape Province. This informed a short co-design process with key stakeholders and service providers to develop local interventions targeted at high priority barriers. Interventions were implemented for 4-6 months and evaluated using theory-based evaluation tools. Clinic service delivery, satisfaction and changes to clinic processes and parent engagement and knowledge were measured. RESULTS: Interventions developed included weekly community immunisation education radio sessions, daily clinic health talks, immunisation education and promotion materials and service provider and parent quality checklists. Evaluation post-intervention showed improvement in parents'/guardians' knowledge about immunisation, parent engagement and service provider commitment to improvement in service quality. Radio sessions and immunisation education and communication materials were deemed most useful by parents and providers. CONCLUSION: Immunisation service delivery can be strengthened using an adaptive, clinic-led assessment process which can effectively identify barriers, inform co-designed interventions and be evaluated over a short period. This approach provides a framework to guide future local participatory action research to more effectively improve childhood immunisation service delivery and other child health services in under-resourced settings.

Influence of human immunodeficiency virus and CD4 count on the prevalence of human papillomavirus in heterosexual couples.

This study investigated the impact of human immunodeficiency virus (HIV) infection on genital human papillomavirus (HPV) in heterosexual couples. More HIV-positive men and women had genital HPV compared with HIV-negative men (77 vs 49%; P<0.001) and women (74 vs 36%; P<0.001). More men and women with partners who were HPV positive had HPV genital infection compared with those with HPV-negative partners (for men, 72% compared with 40%; P<0.001). Men with HIV-positive female partners were at greater risk of high-risk HPV and low-risk HPV (LR HPV) infection compared with men with HIV-negative female partners. This risk increased with decreasing CD4 count { ≥ 350 ml⁻¹: odds ratio [OR ], 2.37 [95% confidence interval (CI), 1.47-3.83]; < 350 ml⁻¹: OR, 3.02 [95 % CI, 1.86-4.9]}. Conversely, the risk of HPV of any type was not found to differ between women with an HIV-positive or HIV-negative male partner. In men, HIV infection and female partner HIV-positive status were both associated with a higher risk of type-specific HPV concordance with their sexual partner, though the associations were not significant for LR HPV. In women, HIV infection and low CD4 count were significantly associated with increased risk of type-specific HPV concordance, but male partner HIV-positive status was not significantly associated with this concordance. In conclusion, male genital HPV prevalence and type-specific sharing were influenced by their own HIV-positive status and that of their female partner. In contrast, female genital HPV prevalence and HPV type-specific sharing were determined by their own HIV-positive status and not by that of their male partner.

Initiation of highly active antiretroviral therapy among pregnant women in Cape Town, South Africa.

OBJECTIVE: To investigate highly active antiretroviral therapy (HAART) initiation among pregnant women and the optimum model of service delivery for integrating HAART services into antenatal care. METHODS: We analysed clinic records to reconstruct a cohort of all HIV-infected pregnant women eligible for HAART at four antenatal clinics representing three service delivery models in Cape Town, South Africa. To assess HAART coverage, records of women determined to be eligible for HAART in pregnancy were reviewed at corresponding HIV treatment services. RESULTS: Of 13,208 pregnant women tested for HIV, 26% were HIV-infected and 15% were HAART-eligible based on a CD4 cell count of

Differences in antiretroviral scale up in three South African provinces: the role of implementation management.

BACKGROUND: South Africa's antiretroviral programme is governed by defined national plans, establishing treatment targets and providing funding through ring-fenced conditional grants. However, in terms of the country's quasi-federal constitution, provincial governments bear the main responsibility for provision of health care, and have a certain amount of autonomy and therefore choice in the way their HIV/AIDS programmes are implemented. METHODS: The paper is a comparative case study of the early management of ART scale up in three South African provincial governments--Western Cape, Gauteng and Free State--focusing on both operational and strategic dimensions. Drawing on surveys of models of ART care and analyses of the policy process conducted in the three provinces between 2005 and 2007, as well as a considerable body of grey and indexed literature on ART scale up in South Africa, it draws links between implementation processes and variations in provincial ART coverage (low, medium and high) achieved in the three provinces. RESULTS: While they adopted similar chronic disease care approaches, the provinces differed with respect to political and managerial leadership of the programme, programme design, the balance between central standardisation and local flexibility, the effectiveness of monitoring and evaluation systems, and the nature and extent of external support and programme partnerships. CONCLUSIONS: This case study points to the importance of sub-national programme processes and the influence of factors other than financing or human resource capacity, in understanding intervention scale up.

Coverage of nevirapine-based services to prevent mother-to-child HIV transmission in 4 African countries.

CONTEXT: Few studies have objectively evaluated the coverage of services to prevent transmission of human immunodeficiency virus (HIV) from mother to child. OBJECTIVE: To measure the coverage of services to prevent mother-to-child HIV transmission in 4 African countries. DESIGN, SETTING, AND PATIENTS: Cross-sectional surveillance study of mother-infant pairs using umbilical cord blood samples collected between June 10, 2007, and October 30, 2008, from 43 randomly selected facilities (grouped as 25 service clusters) providing delivery services in Cameroon, Côte d'Ivoire, South Africa, and Zambia. All sites used at least single-dose nevirapine to prevent mother-to-child HIV transmission and some sites used additional prophylaxis drugs. MAIN OUTCOME MEASURE: Population nevirapine coverage, defined as the proportion of HIV-exposed infants in the sample with both maternal nevirapine ingestion (confirmed by cord blood chromatography) and infant nevirapine ingestion (confirmed by direct observation). RESULTS: A total of 27,893 cord blood specimens were tested, of which 3324 were HIV seropositive (12%). Complete data for cord blood nevirapine results were available on 3196 HIV-seropositive mother-infant pairs. Nevirapine coverage varied significantly by site (range: 0%-82%). Adjusted for country, the overall coverage estimate was 51% (95% confidence interval [CI], 49%-53%). In multivariable analysis, failed coverage of nevirapine-based services was significantly associated with maternal age younger than 20 years (adjusted odds ratio [AOR], 1.44; 95% CI, 1.18-1.76) and maternal age between 20 and 25 years (AOR, 1.28; 95% CI, 1.07-1.54) vs maternal age of older than 30 years; 1 or fewer antenatal care visits (AOR, 2.91; 95% CI, 2.40-3.54), 2 or 3 antenatal care visits (AOR, 1.93; 95% CI, 1.60-2.33), and 4 or 5 antenatal care visits (AOR, 1.56; 95% CI, 1.34-1.80) vs 6 or more antenatal care visits; vaginal delivery (AOR, 1.22; 95% CI, 1.03-1.44) vs cesarean delivery; and infant birth weight of less than 2500 g (AOR, 1.34; 95% CI, 1.11-1.62) vs birth weight of 3500 g or greater. CONCLUSION: In this random sampling of sites with services to prevent mother-to-child HIV transmission, only 51% of HIV-exposed infants received the minimal regimen of single-dose nevirapine.

Impact of human immunodeficiency virus 1 infection and inflammation on the composition and yield of cervical mononuclear cells in the female genital tract.

Cervical cytobrush sampling is a relatively non-invasive method for obtaining mucosal cells from the female genital tract. To define mucosal immune cells sampled by cervical cytobrushing and to validate this approach for local immunity studies, we investigated the impact of human immunodeficiency virus (HIV) status and inflammation on the yield and composition of cervical cytobrush specimens. Cervical cytobrush samples were obtained from 89 chronically HIV-infected and 46 HIV-negative women. The HIV-infected women had significantly higher yields of CD3(+), CD45(+), CD19(+), CD14(+), Langerin(+) and CD24(+) cells than the uninfected women. While cytobrush-derived T cells from uninfected women were predominantly CD4(+) (4.2 CD4 : 1 CD8), CD8(+) T cells were predominant in HIV-infected women (0.6 CD4 : 1 CD8). The majority of CD4(+) and CD8(+) T cells from HIV-infected and uninfected women were of the effector memory (CD45RA(-) CCR7(-) CD27(-)) phenotype. HIV-infected women had significantly elevated levels of interleukin (IL)-1beta, IL-6 and IL-8 in cervical supernatants compared with uninfected women. We observed a significant positive correlation between T-cell counts and IL-1beta, tumour necrosis factor (TNF)-alpha and IL-12 concentrations. Neutrophil counts correlated significantly with cervical concentrations of IL-1beta, TNF-alpha, IL-8, IL-6 and IL-10. Antigen-presenting cell numbers correlated significantly with TNF-alpha and IL-12 concentrations. HIV-infected women on antiretroviral therapy had similar levels of cervical lymphocyte infiltration and inflammation to women naïve to therapy. In conclusion, we suggest that inflammation at the cervix and HIV infection are likely to be key determinants in the absolute number of mucosal immune cells recovered by cervical cytobrushing.