Jordan W. Tappero

Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women

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 participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. CONCLUSIONS Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).

Randomized, Double‐Blind, Placebo‐Controlled Efficacy Trial of a Bivalent Recombinant Glycoprotein 120 HIV‐1 Vaccine among Injection Drug Users in Bangkok, Thailand

BACKGROUND In Thailand, phase 1/2 trials of monovalent subtype B and bivalent subtype B/E (CRF01_AE) recombinant glycoprotein 120 human immunodeficiency virus type 1 (HIV-1) vaccines were successfully conducted from 1995 to 1998, prompting the first HIV-1 vaccine efficacy trial in Asia. METHODS This randomized, double-blind, placebo-controlled efficacy trial of AIDSVAX B/E (VaxGen), which included 36-months of follow-up, was conducted among injection drug users (IDUs) in Bangkok, Thailand. The primary end point was HIV-1 infection; secondary end points included plasma HIV-1 load, CD4 cell count, onset of acquired immunodeficiency syndrome-defining conditions, and initiation of antiretroviral therapy. RESULTS A total of 2546 IDUs were enrolled between March 1999 and August 2000; the median age was 26 years, and 93.4% were men. The overall HIV-1 incidence was 3.4 infections/100 person-years (95% confidence interval [CI], 3.0-3.9 infections/100 person-years), and the cumulative incidence was 8.4%. There were no differences between the vaccine and placebo arms. HIV-1 subtype E (83 vaccine and 81 placebo recipients) accounted for 77% of infections. Vaccine efficacy was estimated at 0.1% (95% CI, -30.8% to 23.8%; P=.99, log-rank test). No statistically significant effects of the vaccine on secondary end points were observed. CONCLUSION Despite the successful completion of this efficacy trial, the vaccine did not prevent HIV-1 infection or delay HIV-1 disease progression.

Isolation of Genetically Diverse Marburg Viruses from Egyptian Fruit Bats

In July and September 2007, miners working in Kitaka Cave, Uganda, were diagnosed with Marburg hemorrhagic fever. The likely source of infection in the cave was Egyptian fruit bats (Rousettus aegyptiacus) based on detection of Marburg virus RNA in 31/611 (5.1%) bats, virus-specific antibody in bat sera, and isolation of genetically diverse virus from bat tissues. The virus isolates were collected nine months apart, demonstrating long-term virus circulation. The bat colony was estimated to be over 100,000 animals using mark and re-capture methods, predicting the presence of over 5,000 virus-infected bats. The genetically diverse virus genome sequences from bats and miners closely matched. These data indicate common Egyptian fruit bats can represent a major natural reservoir and source of Marburg virus with potential for spillover into humans.

Molecular Epidemiology of Bartonella Infections in Patients with Bacillary Angiomatosis–Peliosis

BACKGROUND Bacillary angiomatosis and bacillary peliosis are vascular proliferative manifestations of infection with species of the genus bartonella that occur predominantly in patients infected with the human immunodeficiency virus. Two species, B. henselae and B. quintana, have been associated with bacillary angiomatosis, but culture and speciation are difficult, and there has been little systematic evaluation of the species-specific disease characteristics. We studied 49 patients seen over eight years who were infected with bartonella species identified by molecular techniques and who had clinical lesions consistent with bacillary angiomatosis-peliosis. METHODS In this case-control study, a standardized questionnaire about exposures was administered to patients with bacillary angiomatosis-peliosis and to 96 matched controls. The infecting bartonella species were determined by molecular techniques. RESULTS Of the 49 patients with bacillary angiomatosis-peliosis, 26 (53 percent) were infected with B. henselae and 23 (47 percent) with B. quintana. Subcutaneous and lytic bone lesions were strongly associated with B. quintana, whereas peliosis hepatis was associated exclusively with B. henselae. Patients with B. henselae infection were identified throughout the study period and were epidemiologically linked to cat and flea exposure (P< or =0.004), whereas those with B. quintana were clustered and were characterized by low income (P=0.003), homelessness (P = 0.004), and exposure to lice (P= 0.03). Prior treatment with macrolide antibiotics appeared to be protective against infection with either species. CONCLUSIONS B. henselae and B. quintana, the organisms that cause bacillary angiomatosis-peliosis, are associated with different epidemiologic risk factors and with predilections for involvement of different organs.

Kaposi's sarcoma: Epidemiology, pathogenesis, histology, clinical spectrum, staging criteria and therapy

The acquired immunodeficiency syndrome (AIDS) epidemic has had a profound impact on our understanding of Kaposis sarcoma (KS). Epidemiologic features suggest a sexually transmitted cofactor in the pathogenesis of AIDS-associated KS (AIDS-KS), and several putative agents have received intense scrutiny. Cell culture studies suggest that the angiogenesis of AIDS-KS is stimulated by both human immunodeficiency virus proteins and growth factors that may be involved in the development and progression of AIDS-KS, thereby providing a rationale for new therapeutic interventions. The dermatologist is uniquely qualified to provide care for the majority of patients with KS, as many patients have cutaneous lesions amendable to local therapy (cryotherapy, intralesional therapy, simple excision). Patients requiring more aggressive local therapy (radiation therapy) or systemic therapies (interferon, chemotherapy) can be easily recognized. Standardized staging criteria provide assistance for determining appropriate local or systemic therapy and for evaluating and comparing responses to new therapies. This article reviews the epidemiology, pathogenesis, histologic features, clinical spectrum, staging criteria, and treatment of KS.

Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial

BACKGROUND Identification of new ways to increase access to antiretroviral therapy in Africa is an urgent priority. We assessed whether home-based HIV care was as effective as was facility-based care. METHODS We undertook a cluster-randomised equivalence trial in Jinja, Uganda. 44 geographical areas in nine strata, defined according to ratio of urban and rural participants and distance from the clinic, were randomised to home-based or facility-based care by drawing sealed cards from a box. The trial was integrated into normal service delivery. All patients with WHO stage IV or late stage III disease or CD4-cell counts fewer than 200 cells per microL who started antiretroviral therapy between Feb 15, 2005, and Dec 19, 2006, were eligible, apart from those living on islands. Follow-up continued until Jan 31, 2009. The primary endpoint was virological failure, defined as RNA more than 500 copies per mL after 6 months of treatment. The margin of equivalence was 9% (equivalence limits 0.69-1.45). Analyses were by intention to treat and adjusted for baseline CD4-cell count and study stratum. This trial is registered at http://isrctn.org, number ISRCTN 17184129. FINDINGS 859 patients (22 clusters) were randomly assigned to home and 594 (22 clusters) to facility care. During the first year, 93 (11%) receiving home care and 66 (11%) receiving facility care died, 29 (3%) receiving home and 36 (6%) receiving facility care withdrew, and 8 (1%) receiving home and 9 (2%) receiving facility care were lost to follow-up. 117 of 729 (16%) in home care had virological failure versus 80 of 483 (17%) in facility care: rates per 100 person-years were 8.19 (95% CI 6.84-9.82) for home and 8.67 (6.96-10.79) for facility care (rate ratio [RR] 1.04, 0.78-1.40; equivalence shown). Two patients from each group were immediately lost to follow-up. Mortality rates were similar between groups (0.95 [0.71-1.28]). 97 of 857 (11%) patients in home and 75 of 592 (13%) in facility care were admitted at least once (0.91, 0.64-1.28). INTERPRETATION This home-based HIV-care strategy is as effective as is a clinic-based strategy, and therefore could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care.

Outbreak of Leptospirosis among Triathlon Participants and Community Residents in Springfield, Illinois, 1998

We investigated an outbreak of leptospirosis among athletes and community residents after a triathlon was held in Springfield, Illinois. A telephone survey was conducted to collect clinical information and data on possible risk factors, community surveillance was established, and animal specimens and lake water samples were collected to determine the source of the leptospiral contamination. A total of 834 of 876 triathletes were contacted; 98 (12%) reported being ill. Serum samples obtained from 474 athletes were tested; 52 of these samples (11%) tested positive for leptospirosis. Fourteen (6%) of 248 symptomatic community residents tested positive for leptospirosis. Heavy rains that preceded the triathlon are likely to have increased leptospiral contamination of Lake Springfield. Among athletes, ingestion of 1 or more swallows of lake water was a predominant risk factor for illness. This is the largest outbreak of leptospirosis that has been reported in the United States. Health care providers and occupational and recreational users of bodies of freshwater in the United States should be aware of the risk of contracting leptospirosis, particularly after heavy rains.

Leptospirosis in “Eco-Challenge” Athletes, Malaysian Borneo, 2000

Adventure travel is becoming more popular, increasing the likelihood of contact with unusual pathogens. We investigated an outbreak of leptospirosis in “Eco-Challenge” multisport race athletes to determine illness etiology and implement public health measures. Of 304 athletes, we contacted 189 (62%) from the United States and 26 other countries. Eighty (42%) athletes met our case definition. Twenty-nine (36%) case-patients were hospitalized; none died. Logistic regression showed swimming in the Segama River (relative risk [RR]=2.0; 95% confidence interval [CI]=1.3 to 3.1) to be an independent risk factor. Twenty-six (68%) of 38 case-patients tested positive for leptospiral antibodies. Taking doxycycline before or during the race was protective (RR=0.4, 95% CI=0.2 to 1.2) for the 20 athletes who reported using it. Increased adventure travel may lead to more frequent exposure to leptospires, and preexposure chemoprophylaxis for leptospirosis (200 mg oral doxycycline/week) may decrease illness risk. Efforts are needed to inform adventure travel participants of unique infections such as leptospirosis.

Mortality in HIV-infected Ugandan adults receiving antiretroviral treatment and survival of their HIV-uninfected children: a prospective cohort study

BACKGROUND Antiretroviral therapy (ART) is increasingly available in Africa, but physicians and clinical services are few. We therefore assessed the effect of a home-based ART programme in Uganda on mortality, hospital admissions, and orphanhood in people with HIV-1 and their household members. METHODS In 2001, we enrolled and followed up 466 HIV-infected adults and 1481 HIV-uninfected household members in a prospective cohort study. After 5 months, we provided daily co-trimoxazole (160 mg trimethoprim and 800 mg sulfamethoxazole) prophylaxis to HIV-infected participants. Between May, 2003, and December, 2005, we followed up 138 infected adults who were eligible and 907 new HIV-infected participants and their HIV-negative household members in a study of ART (mainly stavudine, lamivudine, and nevirapine). Households were visited every week by lay providers, and no clinic visits were scheduled after enrolment. We compared rates of death, hospitalisation, and orphanhood during different study periods and calculated the number needed to treat to prevent an outcome. FINDINGS 233 (17%) of 1373 participants with HIV and 40 (1%) of 4601 HIV-uninfected household members died. During the first 16 weeks of ART and co-trimoxazole, mortality in HIV-infected participants was 55% lower than that during co-trimoxazole alone (14 vs 16 deaths per 100 person-years; adjusted hazard ratio 0.45, 95% CI 0.27-0.74, p=0.0018), and after 16 weeks, was reduced by 92% (3 vs 16 deaths per 100 person-years; 0.08, 0.06-0.13, p<0.0001). Compared with no intervention, ART and co-trimoxazole were associated with a 95% reduction in mortality in HIV-infected participants (5 vs 27 deaths per 100 person-years; 0.05, 0.03-0.08, p<0.0001), 81% reduction in mortality in their uninfected children younger than 10 years (0.2 vs 1.2 deaths per 100 person-years; 0.19, 0.06-0.59, p=0.004), and a 93% estimated reduction in orphanhood (0.9 vs 12.8 per 100 person-years of adults treated; 0.07, 0.04-0.13, p<0.0001). INTERPRETATION Expansion of access to ART and co-trimoxazole prophylaxis could substantially reduce mortality and orphanhood among adults with HIV and their families living in resource-poor settings.We conducted this study to find out correlation of CD4% with clinical status in 102 HIV infected antiretroviral naive children. Mean age of presentation was 4.8 years. Perinatal transmission was the commonest mode of transmission (94%). Fever (53%), chronic diarrhea (36%), and cough (29%) were the commonest presenting symptoms. Protein energy malnutrition was seen in 56.7% of children. 33.3% children were asymptomatic, whereas 45.1% were in WHO clinical stages III and IV at the time of presentation. The most common opportunistic infection was tuberculosis. CD4% correlated significantly with the deterioration of the WHO clinical stages (P<0.01) and increasing grades of protein energy malnutrition (P< 0.05).

Reproductive Intentions and Outcomes among Women on Antiretroviral Therapy in Rural Uganda: A Prospective Cohort Study

Background Antiretroviral therapy (ART) may influence the biological, social and behavioral determinants of pregnancy in HIV-infected women. However, there are limited longitudinal data on the reproductive intentions and outcomes among women on ART in Africa. Methodology /Principal Findings Using a prospective cohort design, we analyzed trends in desire for children and predictors of pregnancy among a cohort of 733 HIV-infected women in rural Uganda who initiated ART between May 2003 and May 2004 and were followed up in their homes until June 2006. Women answered in-depth social and behavioral questionnaires administered every quarter in year 1 after initiating ART, and every 6 to 12 months thereafter. Use of family planning methods was assessed at 18 and 24 months after starting ART. We tested for non-constant pregnancy incidence by using a shape parameter test from the Weibull distribution. We modeled repeated measurements of all variables related to the womens desire for children over time using a generalized estimating equation (GEE) extension to the logistic regression model. Risk factors for pregnancy were examined using Cox proportional hazards model. 711 women eligible for the study were followed-up for a median time of 2.4 years after starting ART. During this time, less than 7% of women reported wanting more children at any time point yet 120 (16.9%) women experienced 140 pregnancies and pregnancy incidence increased from 3.46 per 100 women-years (WY) in the first quarter to 9.5 per 100 WY at 24 months (p<0.0001). This was paralleled by an increase in the proportion of women reporting sexual activity in the past 3 months, from 24.4% at baseline to 32.5% over 24 months of follow-up (p = 0.001). Only 14% of women used permanent or semi-permanent family planning methods by their second year on ART. In the multivariate model, younger age (HR = 2.71 per 10-year decrease, 95% CI: 2.95–3.78), having a BMI>18.5 (HR = 1.09, CI: 1.01–1.18) and not having used condoms consistently in the last 3 months (HR = 1.79, CI: 1.02–3.13) were independently associated with pregnancy. Conclusion/Significance Women on ART and their partners should be consistently counseled on the effects of ART in restoring fertility, and offered regularly free and comprehensive family planning services as part of their standard package of care.