Showing papers by "Jared M. Baeten published in 2012"

Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.

Abstract: Background Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. Methods We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1–serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1–seronegative partner in each couple was randomly assigned to one of three study regimens — once-daily tenofovir (TDF), combination tenofovir–emtricitabine (TDF–FTC), or matching placebo — and followed monthly for up to 36 months. At enrollment, the HIV-1–seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. Results We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF–FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1–seronegative partner was male. Among HIV-1–seropositive par...

Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study

Abstract: Summary Background Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. We aimed to assess the association between hormonal contraceptive use and risk of HIV-1 acquisition by women and HIV-1 transmission from HIV-1-infected women to their male partners. Methods In this prospective study, we followed up 3790 heterosexual HIV-1-serodiscordant couples participating in two longitudinal studies of HIV-1 incidence in seven African countries. Among injectable and oral hormonal contraceptive users and non-users, we compared rates of HIV-1 acquisition by women and HIV-1 transmission from women to men. The primary outcome measure was HIV-1 seroconversion. We used Cox proportional hazards regression and marginal structural modelling to assess the effect of contraceptive use on HIV-1 risk. Findings Among 1314 couples in which the HIV-1-seronegative partner was female (median follow-up 18·0 [IQR 12·6–24·2] months), rates of HIV-1 acquisition were 6·61 per 100 person-years in women who used hormonal contraception and 3·78 per 100 person-years in those who did not (adjusted hazard ratio 1·98, 95% CI 1·06–3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8–24·2] months), rates of HIV-1 transmission from women to men were 2·61 per 100 person-years in couples in which women used hormonal contraception and 1·51 per 100 person-years in couples in which women did not use hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12–3·45, p=0·02). Marginal structural model analyses generated much the same results to the Cox proportional hazards regression. Interpretation Women should be counselled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1. Funding US National Institutes of Health and the Bill & Melinda Gates Foundation.

Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples.

Abstract: Background Bacterial vaginosis (BV), a disruption of the normal vaginal flora, has been associated with a 60% increased risk of HIV-1 acquisition in women and higher concentration of HIV-1 RNA in the genital tract of HIV-1–infected women. However, whether BV, which is present in up to half of African HIV-1–infected women, is associated with an increase in HIV-1 transmission to male partners has not been assessed in previous studies. Methods and Findings We assessed the association between BV on female-to-male HIV-1 transmission risk in a prospective study of 2,236 HIV-1–seropositive women and their HIV-1 uninfected male partners from seven African countries from a randomized placebo-controlled trial that enrolled heterosexual African adults who were seropositive for both HIV-1 and herpes simplex virus (HSV)-2, and their HIV-1–seronegative partners. Participants were followed for up to 24 months; every three months, vaginal swabs were obtained from female partners for Gram stain and male partners were tested for HIV-1. BV and normal vaginal flora were defined as a Nugent score of 7–10 and 0–3, respectively. To reduce misclassification, HIV-1 sequence analysis of viruses from seroconverters and their partners was performed to determine linkage of HIV-1 transmissions. Overall, 50 incident HIV-1 infections occurred in men in which the HIV-1–infected female partner had an evaluable vaginal Gram stain. HIV-1 incidence in men whose HIV-1–infected female partners had BV was 2.91 versus 0.76 per 100 person-years in men whose female partners had normal vaginal flora (hazard ratio 3.62, 95% CI 1.74–7.52). After controlling for sociodemographic factors, sexual behavior, male circumcision, sexually transmitted infections, pregnancy, and plasma HIV-1 RNA levels in female partners, BV was associated with a greater than 3-fold increased risk of female-to-male HIV-1 transmission (adjusted hazard ratio 3.17, 95% CI 1.37–7.33). Conclusions This study identified an association between BV and increased risk of HIV-1 transmission to male partners. Several limitations may affect the generalizability of our results including: all participants underwent couples HIV counseling and testing and enrolled in an HIV-1 prevention trial, and index participants had a baseline CD4 count ≥250 cells/mm3 and were HSV-2 seropositive. Given the high prevalence of BV and the association of BV with increased risk of both female HIV-1 acquisition and transmission found in our study, if this association proves to be causal, BV could be responsible for a substantial proportion of new HIV-1 infections in Africa. Normalization of vaginal flora in HIV-1–infected women could mitigate female-to-male HIV-1 transmission. Trial Registration: ClinicalTrials.com NCT00194519 Please see later in the article for the Editors' Summary

Determinants of Per-Coital-Act HIV-1 Infectivity Among African HIV-1–Serodiscordant Couples

Abstract: Background. Knowledge of factors that affect per-act infectivity of human immunodeficiency virus type 1 (HIV-1) is important for designing HIV-1 prevention interventions and for the mathematical modeling of the spread of HIV-1. Methods. We analyzed data from a prospective study of African HIV-1–serodiscordant couples. We assessed transmissions for linkage within the study partnership, based on HIV-1 sequencing. The primary exposure measure was the HIV-1–seropositive partners’ reports of number of sex acts and condom use with their study partner. Results. Of 3297 couples experiencing 86 linked HIV-1 transmissions, the unadjusted per-act risks of unprotected male-to-female (MTF) and female-to-male (FTM) transmission were 0.0019 (95% confidence interval [CI], .0010–.0037) and 0.0010 (95% CI, .00060–.0017), respectively. After adjusting for plasma HIV-1 RNA of the HIV-1–infected partner and herpes simplex virus type 2 serostatus and age of the HIV-1–uninfected partner, we calculated the relative risk (RR) for MTF versus FTM transmission to be 1.03 (P 5 .93). Each log10 increase in plasma HIV-1 RNA increased the per-act risk of transmission by 2.9-fold (95% CI, 2.2–3.8). Self-reported condom use reduced the per-act risk by 78% (RR 5 0.22 [95% CI, .11–.42]). Conclusions. Modifiable risk factors for HIV-1 transmission were plasma HIV-1 RNA level and condom use, and, in HIV-1–uninfected partners, herpes simplex virus 2 infection, genital ulcers, Trichomonas vaginalis, vaginitis or cervicitis, and male circumcision.

What's love got to do with it? Explaining adherence to oral antiretroviral pre-exposure prophylaxis for HIV-serodiscordant couples.

Abstract: OBJECTIVE: Adherence may be the "Achilles heel" of pre-exposure prophylaxis (PrEP) a promising biomedical approach to HIV prevention. This article presents an explanation of PrEP adherence for African serodiscordant couples derived from qualitative data. DESIGN: Explaining quantitative findings is one way qualitative investigation contributes to research in medicine and public health. This qualitative interview study was nested in the Partners PrEP Study a phase III randomized trial evaluating oral tenofovir and emtricitabine/tenofovir PrEP to prevent HIV acquisition by HIV-uninfected partners in serodiscordant heterosexual couples. METHODS: In-depth qualitative interviews were provided by 60 Partners PrEP Study participants in Uganda. Interviews used open-ended questions eliciting information on adherence experiences barriers and facilitators. An inductive approach informed by grounded theory methodology was used to analyze study data. RESULTS: The proposed explanation may be summarized as follows. Serodiscordance destabilizes couples as the HIV-negative partner reacts with anger fear and sadness to the implication of infidelity represented by HIV infection. A "discordance dilemma" ensues as the desire to avoid acquiring HIV and the advantages of preserving the relationship become competing priorities. PrEP is seen as a solution-a means of safeguarding health without ending the relationship. PrEP users benefit from the support of partners who reinforce adherence. Where discord in the relationship persists adherence suffers. CONCLUSIONS: PrEP adherence in serodiscordant couples may be understood as a function of the desire to reduce risk although preserving a partnered relationship. PrEP use in stable couples may be associated with improved adherence and thus greater effectiveness.

Tenofovir-based pre-exposure prophylaxis for HIV prevention: evolving evidence.

Abstract: Purpose of reviewTopical tenofovir gel and oral tenofovir and emtricitabine–tenofovir [FTC/tenofovir disoproxyl fumarate (TDF)] have been demonstrated to have efficacy in preventing HIV-1 in some populations. Preexposure prophylaxis (PrEP) trials and future directions are summarized.Recent findingsP

The impact of early monitored management on survival in hospitalized adult Ugandan patients with severe sepsis: a prospective intervention study*.

Abstract: In sub-Saharan Africa, sepsis is an important cause of mortality. Optimal sepsis management including fluid resuscitation, early antibiotic administration, and patient monitoring is limited by lack of supplies and skilled health workers.Objective:To evaluate whether early, monitored sepsis managemen

HIV-1 Prevention for HIV-1 Serodiscordant Couples

Abstract: A substantial proportion of HIV-1 infected individuals in sub-Saharan Africa are in stable relationships with HIV-1 uninfected partners, and HIV-1 serodiscordant couples thus represent an important target population for HIV-1 prevention. Couple-based HIV-1 testing and counseling facilitates identification of HIV-1 serodiscordant couples, counseling about risk reduction, and referrals to HIV-1 treatment, reproductive health services, and support services. Maximizing HIV-1 prevention for HIV-1 serodiscordant couples requires a combination of strategies, including counseling about condoms, sexual risk, fertility, contraception, and the clinical and prevention benefits of antiretroviral therapy (ART) for the HIV-1-infected partner; provision of clinical care and ART for the HIV-1-infected partner; antenatal care and services to prevent mother-to-child transmission for HIV-1-infected pregnant women; male circumcision for HIV-1-uninfected men; and, pending guidelines and demonstration projects, oral pre-exposure prophylaxis (PrEP) for HIV-1-uninfected partners.

Willingness of Kenyan HIV-1 serodiscordant couples to use antiretroviral-based HIV-1 prevention strategies.

Abstract: Introduction Antiretroviral treatment (ART) and pre-exposure prophylaxis (PrEP) have demonstrated efficacy as new human immunodeficiency virus-1 (HIV-1) prevention approaches for HIV-1 serodiscordant couples. Methods Among Kenyan HIV-1 serodiscordant heterosexual couples participating in a clinical trial of PrEP, we conducted a cross-sectional study and used descriptive statistical methods to explore couples' willingness to use antiretrovirals for HIV-1 prevention. The study was conducted before July 2011, when studies among heterosexual populations reported that ART and PrEP reduced HIV-1 risk. Results For 181 couples in which the HIV-1-infected partner had a CD4 count ≥350 cells per microliter and had not yet initiated ART (and thus did not qualify for ART under Kenyan guidelines), 60.2% of HIV-1 infected partners (69.4% of men and 57.9% of women) were willing to use early ART (at CD4 ≥350 cells per microliter) for HIV-1 prevention. Among HIV-1 uninfected partners, 92.7% (93.8% of men and 86.1% of women) reported willingness to use PrEP. When given a hypothetical choice of early ART or PrEP for HIV-1 prevention, 52.5% of HIV-1-infected participants would prefer to initiate ART early and 56.9% of HIV-1-uninfected participants would prefer to use PrEP. Conclusions Nearly 40% of Kenyan HIV-1-infected individuals in known HIV-1 serodiscordant partnerships reported reservations about early ART initiation for HIV-1 prevention. PrEP interest in this PrEP-experienced population was high. Strategies to achieve high uptake and sustained adherence to ART and PrEP for HIV-1 prevention in HIV-1 serodiscordant couples will require responding to couples' preferences for prevention strategies.

Genital Inflammation Predicts HIV-1 Shedding Independent of Plasma Viral Load and Systemic Inflammation.

Abstract: In women, genital HIV-1 RNA levels predict the risk of HIV-1 transmission independent of plasma viral load. To better understand the factors that contribute to genital HIV-1 shedding, we evaluated the relationships between genital and plasma cytokine concentrations and HIV-1 RNA levels. Vaginal, but not plasma, levels of interferon gamma-induced protein 10 (IP-10) were significantly associated with vaginal viral load, independent of plasma viral load. Thus, efforts to decrease HIV-1 transmission must take into account the role of local inflammation, which is not necessarily reflected in plasma measurements.

Specificity of Four Laboratory Approaches for Cross-Sectional HIV Incidence Determination: Analysis of Samples from Adults with Known Nonrecent HIV Infection from Five African Countries

Abstract: Assays to determine cross-sectional HIV incidence misclassify some individuals with nonrecent HIV infection as recently infected, overestimating HIV incidence. We analyzed factors associated with false-recent misclassification in five African countries. Samples from 2197 adults from Botswana, Kenya, South Africa, Tanzania, and Uganda who were HIV infected >12 months were tested using the (1) BED capture enzyme immunoassay (BED), (2) avidity assay, (3) BED and avidity assays with higher assay cutoffs (BED+avidity screen), and (4) multiassay algorithm (MAA) that includes the BED+avidity screen, CD4 cell count, and HIV viral load. Logistic regression identified factors associated with misclassification. False-recent misclassification rates and 95% confidence intervals were BED alone: 7.6% (6.6, 8.8); avidity assay alone: 3.5% (2.7, 4.3); BED+avidity screen: 2.2% (1.7, 2.9); and MAA: 1.2% (0.8, 1.8). The misclassification rate for the MAA was significantly lower than the rates for the other three met...

Outside sexual partnerships and risk of HIV acquisition for HIV uninfected partners in African HIV serodiscordant partnerships.

Abstract: BACKGROUND: As African countries scale-up couples HIV testing little is known about sexual behaviors and HIV risk for HIV-uninfected partners in known HIV-serodiscordant relationships. METHODS: We conducted a prospective study of 3380 HIV-serodiscordant partnerships from 7 African countries. Self-reported sexual behavior data were collected quarterly from HIV-uninfected partners. RESULTS: The proportion of HIV-uninfected partners reporting sex with their known primary HIV-infected partner decreased during follow-up (from 93.5% in the prior month at baseline to 73.2% at 24 months P < 0.001). Simultaneously an increasing proportion reported sex with an outside partner (from 3.1% to 13.9% P < 0.001). A small proportion (<5% stable throughout follow-up) reported sex with the infected partner and an outside partner in the same month (concurrent). Unprotected sex was more common with outside partners than with their primary known HIV-infected partners (risk ratio 4.6; 95% confidence interval: 4.2 to 5.2). HIV incidence was similar for those reporting sex only with their primary HIV-infected partner compared with those who reported an outside partner (2.87 vs. 3.02 per 100 person-years P = 0.7) although those who had outside partners were more likely to acquire HIV that was virologically distinct from that of their primary partner (P < 0.001). CONCLUSION: For uninfected members of HIV-serodiscordant couples sex with the infected partner declined as sex with outside partners increased likely reflecting relationship dissolution and risk shifting from a known infected partner. Risk-reduction messages for HIV-uninfected partners in serodiscordant partnerships should include strategies to reduce HIV acquisition from outside partners.

Household-Based HIV Counseling and Testing as a Platform for Referral to HIV Care and Medical Male Circumcision in Uganda: A Pilot Evaluation

Abstract: Background Combination HIV prevention initiatives incorporate evidence-based, biomedical and behavioral interventions appropriate and acceptable to specific populations, aiming to significantly reduce population-level HIV incidence. Knowledge of HIV serostatus is key to linkages to HIV care and prevention. Household-based HIV counseling and testing (HBCT) can achieve high HIV testing rates. We evaluated HBCT as a platform for delivery of combination HIV prevention services in sub-Saharan Africa. Methods We conducted HBCT in a semi-urban area in southwestern Uganda. All adults received standard HIV prevention messaging. Real-time electronic data collection included a brief risk assessment and prevention triage algorithm for referrals of HIV seropositive persons to HIV care and uncircumcised HIV seronegative men with multiple sex partners to male circumcision. Monthly follow-up visits for 3 months were conducted to promote uptake of HIV care and male circumcision. Results 855 households received HBCT; 1587 of 1941 (81.8%) adults were present at the HBCT visit, 1557 (98.1% of those present) were tested and received HIV results, of whom, 46.5% were men. A total of 152 (9.8%) were HIV seropositive, for whom the median CD4 count was 456 cells/µL, and 50.7% were newly-identified as HIV seropositive. Three months after HBCT, 88.5% of HIV seropositive persons had attended an HIV care clinic; among those with CD4 counts <250 cells/µL, 71.4% initiated antiretroviral therapy. Among 123 HIV seronegative men with an HIV+ partner or multiple partners, 62.0% were circumcised by month 3. Conclusions HBCT achieves high levels of knowledge of HIV serostatus and is an effective platform for identifying at-risk persons and achieving higher uptake of HIV prevention and care services through referrals and targeted follow-up than has been accomplished through other single focus strategies.

Contraceptive method and pregnancy incidence among women in HIV-1-serodiscordant partnerships.

Abstract: BACKGROUND:: Effective contraception reduces unintended pregnancies and is a central strategy to reduce vertical HIV-1 transmission for HIV-1 infected women METHODS:: Among 2269 HIV-1 seropositive and 1085 seronegative women from 7 African countries who were members of HIV-1 serodiscordant heterosexual partnerships and who were participating in an HIV-1 prevention clinical trial we assessed pregnancy incidence according to contraceptive method using multivariate Andersen-Gill analysis RESULTS:: Compared with women using no contraceptive method pregnancy incidence was significantly reduced among HIV-1 seropositive and seronegative women using injectable contraception (adjusted hazard ratio (aHR) 024 p = 0001 and aHR 025 p < 0001 respectively) Oral contraceptives significantly reduced pregnancy risk only among HIV-1 seropositive women (aHR 051 p = 0004) but not seronegative women (aHR 064 p = 03) and for both seropositive and seronegative women oral contraceptive pill users were more likely to become pregnant than injectable contraceptive users (aHR 222 p = 001 for HIV-1 seropositive women and aHR 265 p = 009 for HIV-1 seronegative women) Condoms when reported as being used as the primary contraceptive method marginally reduced pregnancy incidence (aHR 085 p = 01 for seropositive women and aHR 067 p = 002 for seronegative women) There were no pregnancies among women using intrauterine devices implantable methods or who had undergone surgical sterilization although these methods were used relatively infrequently CONCLUSIONS:: Family planning programs and HIV-1 prevention trials need innovative ways to motivate uptake and sustained use of longer acting less user-dependent contraception for women who do not desire pregnancy

Antiretroviral-Based HIV-1 Prevention: Antiretroviral Treatment and Pre-Exposure Prophylaxis:

Abstract: Antiretroviral-based HIV-1 prevention strategies – including antiretroviral treatment (ART) to reduce the infectiousness of individuals with HIV-1 and oral and topical pre-exposure prophylaxis (PrE...

Oral antiretroviral chemoprophylaxis: current status

Abstract: Purpose of review Preexposure prophylaxis (PrEP), in which HIV uninfected persons with ongoing HIV risk use oral antiretroviral medications as chemoprophylaxis against sexual HIV acquisition, is a promising new HIV prevention strategy. Recent findings During the past 2 years, proof-of-concept that PrEP protects against sexual HIV acquisition has been demonstrated in three clinical trials, conducted among MSM and heterosexual men and women. These trials used daily oral tenofovir disoproxil fumarate, alone or coformulated with emtricitabine. The degree of HIV protection in these trials was strongly related to the level of adherence to PrEP. Two additional clinical trials, both among heterosexual women, did not demonstrate HIV protection with PrEP, with low adherence to daily use of PrEP the leading hypothesis for lack of efficacy; adherence and biologic mechanisms for lack of efficacy in these trial populations are being evaluated. Summary Oral chemoprophylaxis, using tenofovir and combination emtricitabine-tenofovir, is effective for prevention of sexual HIV transmission. Next steps in the field include rigorous evaluation of uptake and adherence to PrEP in implementation settings.

Quantifying Ongoing HIV-1 Exposure in HIV-1–Serodiscordant Couples to Identify Individuals With Potential Host Resistance to HIV-1

Abstract: Background. Immunogenetic correlates of resistance to HIV-1 in HIV-1–exposed seronegative (HESN) individuals with consistently high exposure may inform HIV-1 prevention strategies. We developed a novel approach for quantifying HIV-1 exposure to identify individuals remaining HIV-1 uninfected despite persistent high exposure. Methods. We used longitudinal predictors of HIV-1 transmission in HIV-1 serodiscordant couples to score HIV-1 exposure and define HESN clusters with persistently high, low, and decreasing risk trajectories. The model was validated in an independent cohort of serodiscordant couples. We describe a statistical tool that can be applied to other HESN cohorts to identify individuals with high exposure to HIV-1. Results. HIV-1 exposure was best quantified by frequency of unprotected sex with, plasma HIV-1 RNA levels among, and presence of genital ulcer disease among HIV-1–infected partners and by age, pregnancy status, herpes simplex virus 2 serostatus, and male circumcision status among HESN participants. Overall, 14% of HESN individuals persistently had high HIV-1 exposure and exhibited a declining incidence of HIV-1 infection over time. Conclusions. A minority of HESN individuals from HIV-1–discordant couples had persistent high HIV-1 exposure over time. Decreasing incidence of infection in this group suggests these individuals were selected for resistance to HIV-1 and may be most appropriate for identifying biological correlates of natural host resistance to HIV-1 infection.

Acyclovir Achieves a Lower Concentration in African HIV-Seronegative, Herpes Simplex Virus 2-Seropositive Women than in Non-African Populations

Abstract: Acyclovir pharmacokinetics was evaluated in 68 HIV-seronegative, herpes simplex virus 2 (HSV-2)-seropositive African women, who received a single oral 400-mg dose of acyclovir, with plasma acyclovir concentrations measured over 8 h. Geometric mean peak concentration and area under the concentration-time curve were 0.31 μg/ml and 1.59 h · μg/ml, respectively, 54% and 52% lower than values from non-Africans. Lower acyclovir concentrations may partly explain the reduced acyclovir suppression of HSV-2 genital ulcer recurrence in HPTN 039 African women participants.

Using Plasma Viral Load to Guide Antiretroviral Therapy Initiation to Prevent HIV-1 Transmission

Abstract: Background: Current WHO guidelines recommend antiretroviral therapy (ART) initiation at CD4 counts #350 cells/mL. Increasing this threshold has been proposed, with a primary goal of reducing HIV-1 infectiousness. Because the quantity of HIV-1 in plasma is the primary predictor of HIV-1 transmission, consideration of plasma viral load in ART initiation guidelines is warranted. Methods: Using per-sex-act infectivity estimates and cross-sectional sexual behavior data from 2,484 HIV-1 infected persons with CD4 counts .350 enrolled in a study of African heterosexual HIV-1 serodiscordant couples, we calculated the number of transmissions expected and the number potentially averted under selected scenarios for ART initiation: i) CD4 count ,500 cells/mL, ii) viral load $10,000 or $50,000 copies/mL and iii) universal treatment. For each scenario, we estimated the proportion of expected infections that could be averted, the proportion of infected persons initiating treatment, and the ratio of these proportions. Results: Initiating treatment at viral load $50,000 copies/mL would require treating 19.8% of infected persons with CD4 counts .350 while averting 40.5% of expected transmissions (ratio 2.0); treating at viral load $10,0000 copies/mL had a ratio of 1.5. In contrast, initiation at CD4 count ,500 would require treating 41.8%, while averting 48.4% (ratio 1.1). Conclusion: Inclusion of viral load in ART initiation guidelines could permit targeting ART resources to HIV-1 infected persons who have a higher risk of transmitting HIV-1. Further work is needed to estimate costs and feasibility.

Efficient use of longitudinal CD4 counts and viral load measures in survival analysis

Abstract: CD4 counts and viral loads are dynamic quantities that change with time in HIV-infected persons. Commonly used single summary measures, such as viral load set point or early CD4 count do not explicitly account for changes in viral load or CD4 counts or other features of the overall time course of these measures. However, the efficient use of all repeated measurements within each subject is often a challenge made more difficult by sparse and irregular sampling over time. Here we illustrate how functional principal component (FPC) analysis provides an effective statistical approach for exploiting the patterns in CD4 count and viral load data over time. The method is demonstrated using data from Kenyan women who acquired HIV-1 during follow-up in a high risk cohort and were subsequently followed prospectively from early infection. The FPC scores for each woman obtained by this method serve as informative summary statistics for the CD4-count and viral-load trajectories. Similar to baseline CD4 count or viral set point, the first FPC score can be interpreted as a single-value summary measure of an individual's overall CD4 count or viral load. However, unlike most single-value summaries of CD4-count or viral-load trajectories, the first FPC score summarizes the dynamics of these quantities and is seen to reveal specific features of the trajectories associated with mortality in this cohort. Moreover, FPC scores are shown to be a more powerful prognostic factor than other common summaries when used in survival analysis.

Mortality in members of HIV-1 serodiscordant couples in Africa and implications for antiretroviral therapy initiation: Results of analyses from a multicenter randomized trial

Abstract: The risk of HIV-1 related mortality is strongly related to CD4 count. Guidance on optimal timing for initiation of antiretroviral therapy (ART) is still evolving, but the contribution of HIV-1 infection to excess mortality at CD4 cell counts above thresholds for HIV-1 treatment has not been fully described, especially in resource-poor settings. To compare mortality among HIV-1 infected and uninfected members of HIV-1 serodiscordant couples followed for up to 24 months, we conducted a secondary data analysis examining mortality among HIV-1 serodiscordant couples participating in a multicenter, randomized controlled trial at 14 sites in seven sub-Saharan African countries. Predictors of death were examined using Cox regression and excess mortality by CD4 count and plasma HIV-1 RNA was computed using Poisson regression for correlated data. Among 3295 HIV serodiscordant couples, we observed 109 deaths from any cause (74 deaths among HIV-1 infected and 25 among HIV-1 uninfected persons). Among HIV-1 infected persons, the risk of death increased with lower CD4 count and higher plasma viral levels. HIV-1 infected persons had excess mortality due to medical causes of 15.2 deaths/1000 person years at CD4 counts of 250 – 349 cells/μl and 8.9 deaths at CD4 counts of 350 – 499 cells/μl. Above a CD4 count of 500 cells/μl, mortality was comparable among HIV-1 infected and uninfected persons. Among African serodiscordant couples, there is a high rate of mortality attributable to HIV-1 infection at CD4 counts above the current threshold (200 – 350 cells/μl) for ART initiation in many African countries. These data indicate that earlier initiation of treatment is likely to provide clinical benefit if further expansion of ART access can be achieved. Clinicaltrials.gov (NCT00194519)

Clinical and virologic response to episodic acyclovir for genital ulcers among HIV-1 seronegative, herpes simplex virus type 2 seropositive African women: a randomized, placebo-controlled trial.

Abstract: In a randomized trial among African women with recurrent genital herpes, episodic acyclovir therapy resulted in modestly greater likelihood of lesion healing (HR=1.48, p=0.098; mean 5.1 vs. 6.0 days) and cessation of HSV shedding (HR=1.88, p=0.008; mean 3.0 vs. 5.0 days) compared with placebo, similar to results from high-income countries. (ClinicalTrials.gov registration NCT00808405).