International Dermoscopy Society (IDS) Criteria for Skin Tumors: Validation for Skin of Color Through a Delphi Expert Consensus by the "Imaging in Skin of Color" IDS Task Force.

INTRODUCTION: A structured set of eight basic dermoscopic parameters (lines, clods, dots, circles, pseudopods, structureless, else, and vessels) including a total of 77 variables with corresponding descriptive and metaphoric vocabulary has been released for evaluation of skin tumors by the International Dermoscopy Society (IDS). OBJECTIVES: To validate the aforementioned criteria for the use in darker phototypes (phototypes IV-VI) via an expert consensus. METHODS: The two-round "Delphi method" was adopted, with an iterative process including two rounds of email questionnaires. Potential panelists were asked to take part in the procedure via email on the basis of their expertise in the dermoscopy of skin tumors in dark phototypes. RESULTS: A total of 17 participants were involved. All the original variables of the eight basic parameters reached agreement during the first round, except for "pink small clods" ("milky red globules") and "structureless pink zone" ("milky red areas"). Moreover, during the first round, panelists proposed a change of three existing items and the introduction of four new items, i.e., "black, small clods" ("black globules"), "follicular plugs", "erosions/ulcerations", and "white color around vessels" ("perivascular white halo"). All such proposals achieved agreement, thus being included in the final list, for a total of 79 items. There was consistency between the descriptive and metaphoric approaches in terms of scoring. CONCLUSIONS: Albeit most of the original items were considered applicable even for skin of color, there are some points of differences that physicians need to know. No significant preference was found between descriptive and metaphoric terminology among panelists.

Implementation and Operational Research: Evolution of Couples' Voluntary Counseling and Testing for HIV in Rwanda: From Research to Public Health Practice.

BACKGROUND: Couples' voluntary HIV counseling and testing (CVCT) is a WHO-recommended intervention for prevention of heterosexual HIV transmission which very few African couples have received. We report the successful nationwide implementation of CVCT in Rwanda. METHODS: From 1988 to 1994 in Rwanda, pregnant and postpartum women were tested for HIV and requested testing for their husbands. Partner testing was associated with more condom use and lower HIV and sexually transmitted infection rates, particularly among HIV-discordant couples. After the 1994 genocide, the research team continued to refine CVCT procedures in Zambia. These were reintroduced to Rwanda in 2001 and continually tested and improved. In 2003, the Government of Rwanda (GoR) established targets for partner testing among pregnant women, with the proportion rising from 16% in 2003 to 84% in 2008 as the prevention of mother-to-child transmission program expanded to >400 clinics. In 2009, the GoR adopted joint posttest counseling procedures, and in 2010 a quarterly follow-up program for discordant couples was established in government clinics with training and technical assistance. An estimated 80%-90% of Rwandan couples have now been jointly counseled and tested resulting in prevention of >70% of new HIV infections. CONCLUSIONS: Rwanda is the first African country to have established CVCT as standard of care in antenatal care. More than 20 countries have sent providers to Rwanda for CVCT training. To duplicate Rwanda's success, training and technical assistance must be part of a coordinated effort to set national targets, timelines, indicators, and budgets. Governments, bilateral, and multilateral funding agencies must jointly prioritize CVCT for prevention of new HIV infections.

Transmitted HIV type 1 drug resistance among individuals with recent HIV infection in East and Southern Africa.

To characterize WHO-defined transmitted HIV drug resistance mutation (TDRM) data from recently HIV-infected African volunteers, we sequenced HIV (pol) and evaluated for TDRM the earliest available specimens from ARV-naive volunteers diagnosed within 1 year of their estimated date of infection at eight research centers in sub-Saharan Africa. TDRMs were detected in 19/408 (5%) volunteers. The prevalence of TDRMs varied by research center, from 5/26 (19%) in Entebbe, 6/78 (8%) in Kigali, 2/49 (4%) in Kilifi, to 3/106 (3%) in Lusaka. One of five volunteers from Cape Town (20%) had TDRMs. Despite small numbers, our data suggest an increase in DRMs by year of infection in Zambia (p = 0.004). The prevalence observed in Entebbe was high across the entire study. ARV history data from 12 (63%) HIV-infected sexual partners were available; 3 reported ARV use prior to transmission. Among four partners with sequence data available, transmission linkage was confirmed and two had the same TDRMs as the newly infected volunteer (both K103N). As ARV therapy continues to increase in availability throughout Africa, monitoring incident virus strains for the presence of TDRMs should be a priority. Early HIV infection cohorts provide an excellent and important platform to monitor the development of TDRMs to inform treatment guidelines, drug choices, and strategies for secondary prevention of TDRM transmission.

Safety and immunogenicity study of Multiclade HIV-1 adenoviral vector vaccine alone or as boost following a multiclade HIV-1 DNA vaccine in Africa.

BACKGROUND: We conducted a double-blind, randomized, placebo-controlled Phase I study of a recombinant replication-defective adenovirus type 5 (rAd5) vector expressing HIV-1 Gag and Pol from subtype B and Env from subtypes A, B and C, given alone or as boost following a DNA plasmid vaccine expressing the same HIV-1 proteins plus Nef, in 114 healthy HIV-uninfected African adults. METHODOLOGY/PRINCIPAL FINDINGS: Volunteers were randomized to 4 groups receiving the rAd5 vaccine intramuscularly at dosage levels of 1×10(10) or 1×10(11) particle units (PU) either alone or as boost following 3 injections of the DNA vaccine given at 4 mg/dose intramuscularly by needle-free injection using Biojector® 2000. Safety and immunogenicity were evaluated for 12 months. Both vaccines were well-tolerated. Overall, 62% and 86% of vaccine recipients in the rAd5 alone and DNA prime - rAd5 boost groups, respectively, responded to the HIV-1 proteins by an interferon-gamma (IFN-γ) ELISPOT. The frequency of immune responses was independent of rAd5 dosage levels. The highest frequency of responses after rAd5 alone was detected at 6 weeks; after DNA prime - rAd5 boost, at 6 months (end of study). At baseline, neutralizing antibodies against Ad5 were present in 81% of volunteers; the distribution was similar across the 4 groups. Pre-existing immunity to Ad5 did not appear to have a significant impact on reactogenicity or immune response rates to HIV antigens by IFN-γ ELISPOT. Binding antibodies against Env were detected in up to 100% recipients of DNA prime - rAd5 boost. One volunteer acquired HIV infection after the study ended, two years after receipt of rAd5 alone. CONCLUSIONS/SIGNIFICANCE: The HIV-1 rAd5 vaccine, either alone or as a boost following HIV-1 DNA vaccine, was well-tolerated and immunogenic in African adults. DNA priming increased the frequency and magnitude of cellular and humoral immune responses, but there was no effect of rAd5 dosage on immunogenicity endpoints. TRIAL REGISTRATION: ClinicalTrials.gov NCT00124007.

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.

Knowledge, use, and concerns about contraceptive methods among sero-discordant couples in Rwanda and Zambia.

OBJECTIVE: The unique needs of sero-discordant couples are largely missing from many current family planning efforts, which focus on the prevention of pregnancies in absence of the reduction of the risk of human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Conversely, HIV testing and programs focus exclusively on condom use without discussion of more effective contraceptive methods. In order to provide information to inform the development of family planning services tailored to the unique needs of sero-discordant couples, this study examined the contraceptive knowledge, use, and concerns among sero-discordant couples in urban Rwanda and Zambia. METHODS: This article presents a comparison of family planning knowledge, use, and concerns about contraception among two cohorts of HIV sero-discordant study participants in Rwanda and Zambia. RESULTS: The results reveal an interesting profile of contraceptive knowledge and use among sero-discordant couples; in both settings, despite high levels of knowledge of contraception, use of contraceptive methods remains relatively low. There is a clear gender difference in both the reporting of knowledge and use of contraceptive methods, and there is evidence of clandestine contraceptive use by women. CONCLUSIONS: Including information on family planning in voluntary counseling and testing (VCT) services in addition to tailoring the delivery of family planning information to meet to needs and concerns of HIV-positive women or those with HIV positive partners is an essential step in the delivery of services and prevention efforts to reduce the transmission of HIV. Family planning and HIV prevention programs should integrate counseling on "dual method use," combining condoms for HIV/STI prevention with a long-acting contraceptive for added protection against unplanned pregnancy.

Characteristics of HIV-1 discordant couples enrolled in a trial of HSV-2 suppression to reduce HIV-1 transmission: the partners study.

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 >or=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 log(10) copies/mL. After adjusting for age and African region, correlates of HIV-1 RNA level included male gender (+0.24 log(10) copies/mL; p<0.001) and CD4 count (-0.25 and -0.55 log(10) 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.

CLSI-derived hematology and biochemistry reference intervals for healthy adults in eastern and southern Africa.

BACKGROUND: Clinical laboratory reference intervals have not been established in many African countries, and non-local intervals are commonly used in clinical trials to screen and monitor adverse events (AEs) among African participants. Using laboratory reference intervals derived from other populations excludes potential trial volunteers in Africa and makes AE assessment challenging. The objective of this study was to establish clinical laboratory reference intervals for 25 hematology, immunology and biochemistry values among healthy African adults typical of those who might join a clinical trial. METHODS AND FINDINGS: Equal proportions of men and women were invited to participate in a cross sectional study at seven clinical centers (Kigali, Rwanda; Masaka and Entebbe, Uganda; two in Nairobi and one in Kilifi, Kenya; and Lusaka, Zambia). All laboratories used hematology, immunology and biochemistry analyzers validated by an independent clinical laboratory. Clinical and Laboratory Standards Institute guidelines were followed to create study consensus intervals. For comparison, AE grading criteria published by the U.S. National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) and other U.S. reference intervals were used. 2,990 potential volunteers were screened, and 2,105 (1,083 men and 1,022 women) were included in the analysis. While some significant gender and regional differences were observed, creating consensus African study intervals from the complete data was possible for 18 of the 25 analytes. Compared to reference intervals from the U.S., we found lower hematocrit and hemoglobin levels, particularly among women, lower white blood cell and neutrophil counts, and lower amylase. Both genders had elevated eosinophil counts, immunoglobulin G, total and direct bilirubin, lactate dehydrogenase and creatine phosphokinase, the latter being more pronounced among women. When graded against U.S. -derived DAIDS AE grading criteria, we observed 774 (35.3%) volunteers with grade one or higher results; 314 (14.9%) had elevated total bilirubin, and 201 (9.6%) had low neutrophil counts. These otherwise healthy volunteers would be excluded or would require special exemption to participate in many clinical trials. CONCLUSIONS: To accelerate clinical trials in Africa, and to improve their scientific validity, locally appropriate reference ranges should be used. This study provides ranges that will inform inclusion criteria and evaluation of adverse events for studies in these regions of Africa.

What the better half is thinking: A comparison of men's and women's responses and agreement between spouses regarding reported sexual and reproductive behaviors in Rwanda.

OBJECTIVE: To compare responses to a sexual behavioral survey of spouses in cohabiting heterosexual relationships in Kigali, Rwanda. DESIGN: Cross-sectional survey. METHODS: Husbands and wives in 779 cohabiting couples were interviewed separately with parallel questionnaires. Participants were recruited from a three-year old cohort of 1458 antenatal clinic attendees enrolled in a prospective study in 1988. Analyses compared responses at the gender- and couple-level for agreement and disagreement. RESULTS: Couples were in disagreement more than agreement. Women reported occasionally refusing sex, suggesting condom use, and believing married men were unfaithful. Men reported being in a faithful relationship, greater condom use, and being understanding when wives refused sex. Agreement included relationship characteristics, safety of condoms, and whether condoms had ever been used in the relationship. Disagreement included the preferred timing of next pregnancy, desire for more children, and whether a birth control method was currently used and type of method. CONCLUSIONS: Rwandan husbands and wives differed in sexual behavior and reproductive-related topics. Couple-level reporting provides the most reliable measure for relationship aspects as couples' agreement cannot be assumed among cohabiting partnerships. Furthermore, HIV prevention programs for couples should incorporate communication skills to encourage couple agreement of HIV-related issues.

New heterosexually transmitted HIV infections in married or cohabiting couples in urban Zambia and Rwanda: an analysis of survey and clinical data.

BACKGROUND: Sub-Saharan Africa has a high rate of HIV infection, most of which is attributable to heterosexual transmission. Few attempts have been made to assess the extent of HIV transmission within marriages, and HIV-prevention efforts remain focused on abstinence and non-marital sex. We aimed to estimate the proportion of heterosexual transmission of HIV which occurs within married or cohabiting couples in urban Zambia and Rwanda each year. METHODS: We used population-based data from Demographic and Health Surveys (DHS) on heterosexual behaviour in Zambia in 2001-02 and in Rwanda in 2005. We also used data on the HIV serostatus of married or cohabiting couples and non-cohabiting couples that was collected through a voluntary counselling and testing service for urban couples in Lusaka, in Zambia, and Kigali, in Rwanda. We estimated the probability that an individual would acquire an incident HIV infection from a cohabiting or non-cohabiting sexual partner, and then the proportion of total heterosexual HIV transmission which occurs within married or cohabiting couples in these settings each year. FINDINGS: We analysed DHS data from 1739 Zambian women, 540 Zambian men, 1176 Rwandan women, and 606 Rwandan men. Under our base model, we estimated that 55.1% to 92.7% of new heterosexually acquired HIV infections among adults in urban Zambia and Rwanda occurred within serodiscordant marital or cohabiting relationships, depending on the sex of the index partner and on location. Under our extended model, which incorporated the higher rates of reported condom use that we found with non-cohabiting partners, we estimated that 60.3% to 94.2% of new heterosexually acquired infections occurred within marriage or cohabitation. We estimated that an intervention for couples which reduced transmission in serodiscordant urban cohabiting couples from 20% to 7% every year could avert 35.7% to 60.3% of heterosexually transmitted HIV infections that would otherwise occur. INTERPRETATION: Since most heterosexual HIV transmission for both men and women in urban Zambia and Rwanda takes place within marriage or cohabitation, voluntary counselling and testing for couples should be promoted, as should other evidence-based interventions that target heterosexual couples.

The relationship between alcohol consumption and unprotected sex among known HIV-discordant couples in Rwanda and Zambia.

Although alcohol abuse is highly prevalent in many countries in sub-Saharan Africa, little is known about the relationship between alcohol consumption and risky sexual behavior in these settings. An understanding of this relationship is particularly important given the high prevalence of HIV that exists in many of these countries. This study analyzes data collected from members of cohabiting HIV-discordant couples regarding alcohol consumption and self-reported condom use. After controlling for demographic and socioeconomic co-factors, alcohol use by male partners of HIV-discordant couples was associated with self-reported unprotected sex at follow-up. Counseling about alcohol use should be part of HIV testing and counseling programs, particularly among those found to be HIV-positive.

HIV-infected Rwandan women have a high frequency of long-term survival.

OBJECTIVES: To evaluate rates of long-term survival in a prospective, longitudinal, closed HIV cohort in Africa between 1986 and 2006. METHODS: A total of 548 HIV-infected Rwandan women were recruited from prenatal clinics in Kigali and followed at 3-6 month intervals to February 2006. Overall, 401 women (73%) were HIV positive at initial cross-sectional testing in 1986 (seroprevalent cohort) and 147 women (27%) were initially HIV negative but seroconverted during follow-up from 1986 to 1993 (seroincident cohort). Kaplan-Meier survival methods were used to calculate survival times censored in mid-2003. RESULTS: In February 2006, 109 women (20%) remained alive in the cohort. Time to 50% non-genocide mortality was 11.9 years among seroincident women and 8.9 years among seroprevalent women. Smoothed mortality rates increased with duration of follow-up to a peak of 0.12 deaths per person-year at 9.5 years of follow-up but subsequently declined. After 15 years of follow-up (pre-HAART introduction), the survival probability was 36% for seroincident women and 26% for seroprevalent women. Most survivors had virological and immunological evidence of disease progression. The median CD4 cell count of survivors declined from 447 cells/mul in 1998 to 268 cells/mul in 2003. Among survivors, 57 women (52%) met treatment criteria and initiated antiretroviral treatment by 2006. CONCLUSION: Although median survival times in this cohort were similar to those observed in high-income countries, the rates of long-term survival after 15 years of follow-up were higher than expected. A levelling off of mortality rates during the late stages of follow-up may explain this high rate of long-term survival.

Access to adequate nutrition is a major potential obstacle to antiretroviral adherence among HIV-infected individuals in Rwanda.

Despite the massive expansion of antiretroviral drugs in Africa, little is known about the resulting changes in sexual behavior or obstacles to antiretroviral therapy (ART) adherence. Our evaluation of Rwandan adults on ART found no increase in risky sexual behaviors, but an obstacle to ART initiation and adherence for 76% of patients was a fear of developing too much appetite without enough to eat. Access to adequate nutrition may be a major determinant for long-term adherence to ART.