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1.  Plasma Viral Loads During Early HIV-1 Infection Are Similar in Subtype C– and Non-Subtype C–Infected African Seroconverters 
The Journal of Infectious Diseases  2013;207(7):1166-1170.
Recent data suggest that infection with human immunodeficiency virus type 1 (HIV-1) subtype C results in prolonged high-level viremia (>5 log10 copies/mL) during early infection. We examined the relationship between HIV-1 subtype and plasma viremia among 153 African seroconverters. Mean setpoint viral loads were similar for C and non-C subtypes: 4.36 vs 4.42 log10 copies/mL (P = .61). The proportion of subtype C–infected participants with viral loads >5 log10 copies/mL was not greater than the proportion for those with non-C infection. Our data do not support the hypothesis that higher early viral load accounts for the rapid spread of HIV-1 subtype C in southern Africa.
doi:10.1093/infdis/jit015
PMCID: PMC3583276  PMID: 23315322
HIV-1; group M subtype; plasma viral load; early infection; Africa
2.  HIV Testing and Counseling Leads to Immediate Consistent Condom Use among South African Stable HIV-discordant Couples 
Introduction
Effective behavioral HIV prevention is needed for stable HIV-discordant couples at risk for HIV, especially those without access to biomedical prevention. This analysis addressed whether HIV testing and counseling (HTC) with ongoing counseling and condom distribution lead to reduced unprotected sex in HIV-discordant couples.
Methods
Partners in Prevention HSV/HIV Transmission Study was a randomized trial conducted from 2004–2008 assessing whether acyclovir reduced HIV transmission from HSV-2/HIV-1 co-infected persons to HIV-uninfected sex partners. This analysis relied on self-reported behavioral data from 508 HIV-infected South African participants. The exposure was timing of first HTC: 0–7, 8–14, 15–30, or >30 days before baseline. In each exposure group, predicted probabilities of unprotected sex in the last month were calculated at baseline, month one, and month twelve using generalized estimating equations with a logit link and exchangeable correlation matrix.
Results
At baseline, participants who knew their HIV status for less time experienced higher predicted probabilities of unprotected sex in the last month: 0–7 days, 0.71; 8–14 days, 0.52; 15–30 days, 0.49; >30 days, 0.26. At month one, once all participants had been aware of being in HIV-discordant relationships for ≥ 1 month, predicted probabilities declined: 0–7 days, 0.08; 8–14 days, 0.08; 15–30 days, 0.15; >30 days, 0.14. Lower predicted probabilities were sustained through month twelve: 0–7 days, 0.08; 8–14 days, 0.11; 15–30 days, 0.05; >30 days, 0.19.
Conclusions
Unprotected sex declined after HIV-positive diagnosis, and declined further after awareness of HIV-discordance. Identifying HIV-discordant couples for behavioral prevention is important for reducing HIV transmission risk.
doi:10.1097/QAI.0b013e31827971ca
PMCID: PMC3548982  PMID: 23117500
HIV; condom; unprotected sex; HIV counseling and testing; discordant couple; South Africa
3.  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.
doi:10.1186/1471-2334-14-51
PMCID: PMC3922074  PMID: 24484380
Human papillomavirus; Human immunodeficiency virus; Viral load
4.  Measuring Coverage in MNCH: Population HIV-Free Survival among Children under Two Years of Age in Four African Countries 
PLoS Medicine  2013;10(5):e1001424.
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.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
For a pregnant woman who is HIV-positive, the discrepancy across the world in outlook for mother and child is stark. Mother-to-child transmission of HIV during pregnancy is now less than 1% in many high-income settings, but occurs much more often in low-income countries. Three interventions have a major impact on transmission of HIV to the baby: antiretroviral drugs, mode of delivery, and type of infant feeding. The latter two are complex, as the interventions commonly used in high-income countries (cesarean section if the maternal viral load is high; exclusive formula feeding) have their own risks in low-income settings. Minimizing the risks of transmitting HIV through effective drug regimes therefore becomes particularly important. Monitoring progress on reducing the incidence of mother-to-child HIV transmission is essential, but not always easy to achieve.
Why Was This Study Done?
A research group led by Stringer and colleagues recently reported a study from four countries in Africa: Cameroon, Côte D'Ivoire, South Africa, and Zambia. The study showed that even in the health facility setting (e.g., hospitals and clinics), only half of infants whose mothers were HIV-positive received the minimum recommended drug treatment (one dose of nevirapine during labor) to prevent HIV transmission. Across the population of these countries, it is possible that fewer receive antiretroviral drugs, as the study did not include women who did not access health facilities. Therefore, the next stage of the study by this research group, reported here, involved going into the communities around these health facilities to find out how many infants under two years old had been exposed to HIV, whether they had received drugs to prevent transmission, and what proportion were alive and not infected with HIV at two years old.
What Did the Researchers Do and Find?
The researchers tested all consenting women who had delivered a baby in the last two years in the surrounding communities. If the mother was found to be HIV-positive, then the infant was also tested for HIV. The researchers then calculated how many of the infants would be alive at two years and free of HIV infection.
Most mothers (78%) agreed to testing for themselves and their infants. There were 7,985 children under two years of age in this study, of whom 13% had been born to an HIV-positive mother. Less than half (46%) of the HIV-positive mothers had received any drugs to prevent HIV transmission. Of the children with HIV-positive mothers, 11% were HIV-infected, 84% were not infected with HIV, and 5% had died. Overall, the researchers estimated that around 80% of these children would be alive at two years without HIV infection. This proportion differed non-significantly between the four countries (ranging from 73% to 84%). The researchers found higher rates of infant survival than they had expected and knew that they might have missed some infant deaths (e.g., if households with infant deaths were less likely to take part in the study).
The researchers found that their estimates of the proportion of HIV-positive mothers who received drugs to prevent transmission were fairly similar between their previous study, looking at health facilities, and this study of the surrounding communities. However, in 14 out of 16 comparisons, the estimate from the community was lower than that from the facility.
What Do These Findings Mean?
This study shows that it would be possible to estimate how many infants are surviving free of HIV infection using a study based in the community, and that these estimates may be more accurate than those for studies based in health facilities. There are still a large proportion of HIV-positive mothers who are not receiving drugs to prevent transmission to the baby. The authors suggest that using two or three drugs to prevent HIV may help to reduce transmission.
There are already community surveys conducted in many low-income countries, but they have not included routine infant testing for HIV. It is now essential that organizations providing drugs, money, and infrastructure in this field consider more accurate means of monitoring incidence of HIV transmission from mother to infant, particularly at the community level.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001424.
The World Health Organization has more information on mother-to-child transmission of HIV
The United Nations Children's Fund has more information on the status of national PMTCT responses in the most affected countries
doi:10.1371/journal.pmed.1001424
PMCID: PMC3646218  PMID: 23667341
5.  A Recent HIV Diagnosis Is Associated with Non-Completion of Isoniazid Preventive Therapy in an HIV-Infected Cohort in Cape Town 
PLoS ONE  2012;7(12):e52489.
Introduction
Despite high rates of successful treatment TB incidence in South Africa remains high, suggesting ongoing transmission and a large reservoir of latently infected persons. Isoniazid preventive therapy (IPT) is recommended as preventive therapy in HIV-infected persons. However, implementation has been slow, impeded by barriers and challenges including the fear of non-adherence.
Objective and Methods
The aim was to evaluate predictors of IPT non-completion. One hundred and sixty four antiretroviral therapy (ART)-naïve HIV-infected patients with tuberculin skin test ≥5 mm were recruited from Khayelitsha day hospital and followed up monthly. A questionnaire was used to collect demographic information.
Results
The overall completion rate was 69%. In multivariable analysis, there was a 29% decrease in risk of non-completion for every year after HIV diagnosis (OR 0.81; 95% C.I. 0.68–0.98). Self-reported alcohol drinkers (OR 4.05; 95% C.I. 1.89–9.06) also had a four-fold higher risk of non-completion, with a strong association between alcohol drinkers and smoking (χ2 27.08; p<0.001).
Conclusion
We identify patients with a recent HIV diagnosis, in addition to self-reported drinkers and smokers as being at higher risk of non-completion of IPT. The period of time since HIV diagnosis should therefore be taken into account when initiating IPT. Our results also suggest that smokers and alcohol drinkers should be identified and targeted for adherence interventions when implementing IPT on a wider scale.
doi:10.1371/journal.pone.0052489
PMCID: PMC3527556  PMID: 23285064
6.  Immune Activation in the Female Genital Tract During HIV Infection Predicts Mucosal CD4 Depletion and HIV Shedding 
The Journal of Infectious Diseases  2011;204(10):1550-1556.
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.
doi:10.1093/infdis/jir591
PMCID: PMC3192190  PMID: 21940422
7.  The Effect of Complete Integration of HIV and TB Services on Time to Initiation of Antiretroviral Therapy: A Before-After Study 
PLoS ONE  2012;7(10):e46988.
Background
Studies have shown that early ART initiation in TB/HIV co-infected patients lowers mortality. One way to implement earlier ART commencement could be through integration of TB and HIV services, a more efficient model of care than separate, vertical programs. We present a model of full TB/HIV integration and estimate its effect on time to initiation of ART.
Methodology/Principal Findings
We retrospectively reviewed TB registers and clinical notes of 209 TB/HIV co-infected adults with a CD4 count <250 cells/µl and registered for TB treatment at one primary care clinic in a South African township between June 2008 and May 2009. Using Kaplan-Meier and Cox proportional hazard analysis, we compared time between initiation of TB treatment and ART for the periods before and after full, “one-stop shop” integration of TB and HIV services (in December 2009). Potential confounders were determined a priori through directed acyclic graphs. Robustness of assumptions was investigated by sensitivity analyses. The analysis included 188 patients (100 pre- and 88 post-integration), yielding 56 person-years of observation. Baseline characteristics of the two groups were similar. Median time to ART initiation decreased from 147 days (95% confidence interval [CI] 85–188) before integration of services to 75 days (95% CI 52–119) post-integration. In adjusted analyses, patients attending the clinic post-integration were 1.60 times (95% CI 1.11–2.29) more likely to have started ART relative to the pre-integration period. Sensitivity analyses supported these findings.
Conclusions/Significance
Full TB/HIV care integration is feasible and led to a 60% increased chance of co-infected patients starting ART, while reducing time to ART initiation by an average of 72 days. Although these estimates should be confirmed through larger studies, they suggest that scale-up of full TB/HIV service integration in high TB/HIV prevalence settings may shorten time to ART initiation, which might reduce excess mortality and morbidity.
doi:10.1371/journal.pone.0046988
PMCID: PMC3465310  PMID: 23071690
8.  High yield of culture-based diagnosis in a TB-endemic setting 
BMC Infectious Diseases  2012;12:218.
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.
doi:10.1186/1471-2334-12-218
PMCID: PMC3482573  PMID: 22978323
Tuberculosis; Diagnosis; Culture; Microscopy
9.  Health Facility Characteristics and Their Relationship to Coverage of PMTCT of HIV Services across Four African Countries: The PEARL Study 
PLoS ONE  2012;7(1):e29823.
Background
Health facility characteristics associated with effective prevention of mother-to-child transmission of HIV (PMTCT) coverage in sub-Saharan are poorly understood.
Methodology/Principal Findings
We conducted surveys in health facilities with active PMTCT services in Cameroon, Cote d'Ivoire, South Africa, and Zambia. Data was compiled via direct observation and exit interviews. We constructed composite scores to describe provision of PMTCT services across seven topical areas: antenatal quality, PMTCT quality, supplies available, patient satisfaction, patient understanding of medication, and infrastructure quality. Pearson correlations and Generalized Estimating Equations (GEE) to account for clustering of facilities within countries were used to evaluate the relationship between the composite scores, total time of visit and select individual variables with PMTCT coverage among women delivering.
Between July 2008 and May 2009, we collected data from 32 facilities; 78% were managed by the government health system. An opt-out approach for HIV testing was used in 100% of facilities in Zambia, 63% in Cameroon, and none in Côte d'Ivoire or South Africa. Using Pearson correlations, PMTCT coverage (median of 55%, (IQR: 33–68) was correlated with PMTCT quality score (rho = 0.51; p = 0.003); infrastructure quality score (rho = 0.43; p = 0.017); time spent at clinic (rho = 0.47; p = 0.013); patient understanding of medications score (rho = 0.51; p = 0.006); and patient satisfaction quality score (rho = 0.38; p = 0.031). PMTCT coverage was marginally correlated with the antenatal quality score (rho = 0.304; p = 0.091). Using GEE adjustment for clustering, the, antenatal quality score became more strongly associated with PMTCT coverage (p<0.001) and the PMTCT quality score and patient understanding of medications remained marginally significant.
Conclusions/Results
We observed a positive relationship between an antenatal quality score and PMTCT coverage but did not identify a consistent set of variables that predicted PMTCT coverage.
doi:10.1371/journal.pone.0029823
PMCID: PMC3262794  PMID: 22276130
10.  Correcting for Mortality Among Patients Lost to Follow Up on Antiretroviral Therapy in South Africa: A Cohort Analysis 
PLoS ONE  2011;6(2):e14684.
Background
Loss to follow-up (LTF) challenges the reporting of antiretroviral treatment (ART) programmes, since it encompasses patients alive but lost to programme and deaths misclassified as LTF. We describe LTF before and after correction for mortality in a primary care ART programme with linkages to the national vital registration system.
Methods and Findings
We included 6411 patients enrolled on ART between March 2001 and June 2007. Patients LTF with available civil identification numbers were matched with the national vital registration system to ascertain vital status. Corrected mortality and true LTF were determined by weighting these patients to represent all patients LTF. We used Kaplan-Meier estimates and Cox regression to describe LTF, mortality among those LTF, and true LTF. Of 627 patients LTF, 85 (28.8%) had died within 3 months after their last clinic visits. Respective estimates of LTF before and after correction for mortality were 6.9% (95% confidence interval [CI] 6.2–7.6) and 4.3% (95% CI 3.5–5.3) at one year on ART, and 23.9% (95% CI 21.0–27.2) and 19.7% (95% CI 16.1–23.7) at 5 years. After correction for mortality, the hazard of LTF was reversed from decreasing to increasing with time on ART. Younger age, higher baseline CD4 count, pregnancy and increasing calendar year were associated with higher true LTF. Mortality of patients LTF at 1, 12 and 24 months after their last visits was respectively 23.1%, 30.9% and 43.8%; 78.0% of deaths occurred during the first 3 months after last visit and 45.0% in patients on ART for 0 to 3 months.
Conclusions
Mortality of patients LTF was high and occurred early after last clinic visit, especially in patients recently started on ART. Correction for these misclassified deaths revealed that the risk of true LTF increased over time. Research targeting groups at higher risk of LTF (youth, pregnant women and patients with higher CD4 counts) is needed.
doi:10.1371/journal.pone.0014684
PMCID: PMC3040750  PMID: 21379378
11.  Epidemic Levels of Drug Resistant Tuberculosis (MDR and XDR-TB) in a High HIV Prevalence Setting in Khayelitsha, South Africa 
PLoS ONE  2010;5(11):e13901.
Background
Although multidrug-resistant tuberculosis (MDR-TB) is emerging as a significant threat to tuberculosis control in high HIV prevalence countries such as South Africa, limited data is available on the burden of drug resistant tuberculosis and any association with HIV in such settings. We conducted a community-based representative survey to assess the MDR-TB burden in Khayelitsha, an urban township in South Africa with high HIV and TB prevalence.
Methodology/Principal Findings
A cross-sectional survey was conducted among adult clinic attendees suspected for pulmonary tuberculosis in two large primary care clinics, together constituting 50% of the tuberculosis burden in Khayelitsha. Drug susceptibility testing (DST) for isoniazid and rifampicin was conducted using a line probe assay on positive sputum cultures, and with culture-based DST for first and second-line drugs. Between May and November 2008, culture positive pulmonary tuberculosis was diagnosed in 271 new and 264 previously treated tuberculosis suspects (sample enriched with previously treated cases). Among those with known HIV status, 55% and 71% were HIV infected respectively. MDR-TB was diagnosed in 3.3% and 7.7% of new and previously treated cases. These figures equate to an estimated case notification rate for MDR-TB of 51/100,000/year, with new cases constituting 55% of the estimated MDR-TB burden. HIV infection was not significantly associated with rifampicin resistance in multivariate analyses.
Conclusions/Significance
There is an extremely high burden of MDR-TB in this setting, most likely representing ongoing transmission. These data highlight the need to diagnose drug resistance among all TB cases, and for innovative models of case detection and treatment for MDR-TB, in order to interrupt transmission and control this emerging epidemic.
doi:10.1371/journal.pone.0013901
PMCID: PMC2981525  PMID: 21085569
12.  Differences in antiretroviral scale up in three South African provinces: the role of implementation management 
BMC Health Services Research  2010;10(Suppl 1):S4.
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.
doi:10.1186/1472-6963-10-S1-S4
PMCID: PMC2895748  PMID: 20594370
13.  Daily Acyclovir Delays HIV-1 Disease Progression Among HIV-1/HSV-2 Dually-Infected Persons: A Randomized Trial 
Lancet  2010;375(9717):824-833.
Background
Well-tolerated medications that slow HIV-1 disease progression and delay initiation of antiretroviral therapy (ART) are needed. Most HIV-1-infected persons are dually-infected with herpes simplex virus type 2 (HSV-2). Daily HSV-2 suppression reduces plasma HIV-1 levels, but whether HSV-2 suppression delays HIV-1 disease progression is unknown.
Methods
Within a randomized, placebo-controlled trial of HSV-2 suppressive therapy (acyclovir 400 mg orally bid) to decrease HIV-1 transmission, 3381 HSV-2/HIV-1 dually-infected heterosexual Africans who at enrollment had CD4 counts ≥250 cells/mm3 and were not taking ART were followed for up to 24 months. We evaluated the effect of acyclovir on HIV-1 disease progression, defined by a primary composite endpoint of first occurrence of CD4 count <200 cells/mm3, ART initiation, or non-trauma related death. As an exploratory analysis, we evaluated the endpoint of CD4 decline to <350 cells/mm3.
Findings
At enrollment, median CD4 was 462 cells/mm3 and median HIV-1 plasma RNA was 4.1 log10 copies/mL. Acyclovir reduced risk of HIV-1 disease progression: 284 participants on acyclovir versus 324 on placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.71–0.98, p=0.03). Among participants with CD4 counts ≥350 cells/mm3, acyclovir delayed risk of CD4 decline to <350 cells/mm3 (HR 0.81, 95% CI 0.71–0.93, p=0.002).
Interpretation
HSV-2 suppression with acyclovir reduced the risk of HIV-1 disease progression by 16% (95% CI 2–29%). The role of HSV-2 suppression in reducing HIV-1 disease progression prior to ART initiation warrants consideration (ClinicalTrials.gov #NCT00194519).
doi:10.1016/S0140-6736(09)62038-9
PMCID: PMC2877592  PMID: 20153888
HIV-1 disease progression; HIV-1 discordant couples; HSV-2; genital herpes; herpes suppression; acyclovir; randomized clinical trial
14.  Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2 
The New England journal of medicine  2010;362(5):427-439.
BACKGROUND
Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1.
METHODS
We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, ≥250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses.
RESULTS
A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P = 0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log10 copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2–positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed.
CONCLUSIONS
Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log10 copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)
doi:10.1056/NEJMoa0904849
PMCID: PMC2838503  PMID: 20089951
15.  Partner notification for the control of sexually transmitted infections 
BMJ : British Medical Journal  2007;334(7589):323.
Assisting patients in disclosing their diagnosis to partners is the biggest priority
doi:10.1136/bmj.39114.635405.80
PMCID: PMC1801013  PMID: 17303839
16.  Characteristics of HIV-1 Discordant Couples Enrolled in a Trial of HSV-2 Suppression to Reduce HIV-1 Transmission: The Partners Study 
PLoS ONE  2009;4(4):e5272.
Background
The Partners HSV-2/HIV-1 Transmission Study (Partners Study) is a phase III, placebo-controlled trial of daily acyclovir for genital herpes (HSV-2) suppression among HIV-1/HSV-2 co-infected persons to reduce HIV-1 transmission to their HIV-1 susceptible partners, which requires recruitment of HIV-1 serodiscordant heterosexual couples. We describe the baseline characteristics of this cohort.
Methods
HIV-1 serodiscordant heterosexual couples, in which the HIV-1 infected partner was HSV-2 seropositive, had a CD4 count ≥250 cells/mcL and was not on antiretroviral therapy, were enrolled at 14 sites in East and Southern Africa. Demographic, behavioral, clinical and laboratory characteristics were assessed.
Results
Of the 3408 HIV-1 serodiscordant couples enrolled, 67% of the HIV-1 infected partners were women. Couples had cohabitated for a median of 5 years (range 2–9) with 28% reporting unprotected sex in the month prior to enrollment. Among HIV-1 susceptible participants, 86% of women and 59% of men were HSV-2 seropositive. Other laboratory-diagnosed sexually transmitted infections were uncommon (<5%), except for Trichomonas vaginalis in 14% of HIV-1 infected women. Median baseline CD4 count for HIV-1 infected participants was 462cells/mcL and median HIV-1 plasma RNA was 4.2 log10 copies/mL. After adjusting for age and African region, correlates of HIV-1 RNA level included male gender (+0.24 log10 copies/mL; p<0.001) and CD4 count (−0.25 and −0.55 log10 copies/mL for CD4 350–499 and >500 relative to <350, respectively, p<0.001).
Conclusions
The Partners Study successfully enrolled a cohort of 3408 heterosexual HIV-1 serodiscordant couples in Africa at high risk for HIV-1 transmission. Follow-up of this cohort will evaluate the efficacy of acyclovir for HSV-2 suppression in preventing HIV-1 transmission and provide insights into biological and behavioral factors determining heterosexual HIV-1 transmission.
Trial Registration
ClinicalTrials.gov NCT00194519
doi:10.1371/journal.pone.0005272
PMCID: PMC2671170  PMID: 19404392
17.  Impact of Mucosal Inflammation on Cervical Human Immunodeficiency Virus (HIV-1)-Specific CD8 T-Cell Responses in the Female Genital Tract during Chronic HIV Infection▿  
Journal of Virology  2008;82(17):8529-8536.
The female genital tract is the major route of heterosexual human immunodeficiency virus (HIV) acquisition and transmission. Here, we investigated whether HIV-specific CD8 T-cell-mediated immune responses could be detected in the genital mucosa of chronically HIV-infected women and whether these were associated with either local mucosal HIV shedding or local immune factors. We found that CD8+ T-cell gamma interferon responses to Gag were detectable at the cervix of HIV-infected women but that the magnitude of genital responses did not correlate with those similarly detected in blood. This indicates that ex vivo HIV responses in one compartment may not be predictive of those in the other. We found that increased genital tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) levels correlated significantly with levels of Gag-specific CD8+ T cells at the cervix. Women who were detectably shedding virus in the genital tract had significantly increased cervical levels of TNF-α, IL-1β, IL-6, and IL-8 compared to women who were not detectably shedding virus. We were, however, unable to detect any association between the magnitude of cervical HIV-specific responses and mucosal HIV shedding. Our results support the hypothesis that proinflammatory cytokines in the female genital tract may promote HIV replication and shedding. In addition, we further show that inflammatory cytokines are associated with increased levels of HIV-specific CD8 effector cells at the genital mucosa but that these were not able to control genital HIV shedding.
doi:10.1128/JVI.00183-08
PMCID: PMC2519691  PMID: 18562528
18.  Regional Differences in Prevalence of HIV-1 Discordance in Africa and Enrollment of HIV-1 Discordant Couples into an HIV-1 Prevention Trial 
PLoS ONE  2008;3(1):e1411.
Background
Most HIV-1 transmission in Africa occurs among HIV-1-discordant couples (one partner HIV-1 infected and one uninfected) who are unaware of their discordant HIV-1 serostatus. Given the high HIV-1 incidence among HIV-1 discordant couples and to assess efficacy of interventions for reducing HIV-1 transmission, HIV-1 discordant couples represent a critical target population for HIV-1 prevention interventions and prevention trials. Substantial regional differences exist in HIV-1 prevalence in Africa, but regional differences in HIV-1 discordance among African couples, has not previously been reported.
Methodology/Principal Findings
The Partners in Prevention HSV-2/HIV-1 Transmission Trial (“Partners HSV-2 Study”), the first large HIV-1 prevention trial in Africa involving HIV-1 discordant couples, completed enrollment in May 2007. Partners HSV-2 Study recruitment data from 12 sites from East and Southern Africa were used to assess HIV-1 discordance among couples accessing couples HIV-1 counseling and testing, and to correlate with enrollment of HIV-1 discordant couples. HIV-1 discordance at Partners HSV-2 Study sites ranged from 8–31% of couples tested from the community. Across all study sites and, among all couples with one HIV-1 infected partner, almost half (49%) of couples were HIV-1 discordant. Site-specific monthly enrollment of HIV-1 discordant couples into the clinical trial was not directly associated with prevalence of HIV-1 discordance, but was modestly correlated with national HIV-1 counseling and testing rates and access to palliative care/basic health care (r = 0.74, p = 0.09).
Conclusions/Significance
HIV-1 discordant couples are a critical target for HIV-1 prevention in Africa. In addition to community prevalence of HIV-1 discordance, national infrastructure for HIV-1 testing and healthcare delivery and effective community outreach strategies impact recruitment of HIV-1 discordant couples into HIV-1 prevention trials.
doi:10.1371/journal.pone.0001411
PMCID: PMC2156103  PMID: 18183292
19.  Sensitivity Analysis and Potential Uses of a Novel Gamma Interferon Release Assay for Diagnosis of Tuberculosis 
Journal of Clinical Microbiology  2006;44(8):2844-2850.
Sputum smears for acid-fast bacilli (AFB) are the primary methods for diagnosis of tuberculosis (TB) in many countries. The tuberculin skin test (TST) is the primary method for diagnosis of latent TB infection (LTBI) worldwide. The poor sensitivity of the former and the poor specificity of the latter warrant the development of new tests and strategies to enhance diagnostic capabilities. We evaluated the sensitivity of an “in-tube” gamma interferon release assay (IGRA) using TB-specific antigens in comparison to the TST and the sputum smear for AFB in TB cases in South Africa. The sensitivity of the IGRA for TB was considered a surrogate of sensitivity in LTBI. Among 154 patients with a positive culture for Mycobacterium tuberculosis, the sensitivity of the IGRA for the diagnosis of TB varied by clinical subgroup from 64% to 82%, that of the TST varied from 85% to 94%, and that of two sputum smears for AFB varied from 35% to 53%. The sensitivity of the IGRA in human immunodeficiency virus (HIV)-infected TB cases was 81%. HIV-infected TB patients were significantly more likely to have indeterminate IGRA results and produced quantitatively less gamma interferon in response to TB-specific antigens than HIV-negative TB patients. The overall sensitivity of the TST in all TB cases was higher than that of the IGRA (90% versus 76%, respectively). The combined sensitivities of the TST plus IGRA and TST plus a single sputum smear were 96% and 93%, respectively. The TST combined with IGRA or with a single sputum smear may have a role in excluding the diagnosis of TB in some settings.
doi:10.1128/JCM.02411-05
PMCID: PMC1594653  PMID: 16891501

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