Cynthia Firnhaber

The prevalence of hepatitis B co-infection in a South African urban government HIV clinic

OBJECTIVE There are an estimated 350 million hepatitis B carriers worldwide. In South Africa the prevalence of mono-infection with hepatitis B has been estimated to range from 1% in urban areas to approximately 10% in rural areas. The exact prevalence of hepatitis B in the HIV-infected population has not been well established. Hepatitis B screening is not standard practice in government HIV clinics. Co-infection with hepatitis B and HIV can influence antiretroviral treatment and prognosis of both diseases. The purpose of this study was to evaluate the prevalence of hepatitis B/HIV coinfection. DESIGN This is believed to be the first prospective observational report on the prevalence of hepatitis B/HIV co-infection in South Africa. Patients on whom hepatitis B serological tests could not have been done previously were recruited from an HIV clinic in a regional hospital in Johannesburg. Standard hepatitis B serological tests were performed. RESULTS Five hundred and two participants were screened. The cohorts average age was 37 +/- 9 years and the average CD4 count was 128 cells/pi. Twenty-four (4.80%) were hepatitis B surface antigen positive. Nearly half (47%) of the participants showed some evidence of hepatitis B exposure. The risk of hepatitis B co-infection was not significantly different when analysed in terms of sex, race, CD4 count or age. Liver function tests were not a good predictor of hepatitis B infection. CONCLUSION The rate of hepatitis B infection, as defined by hepatitis B surface antigen positivity in HIV-infected individuals in urban South Africa was 5 times the rate in people who were not HIV-infected. A 5% rate of hepatitis B/HIV co-infection is a reason to increase the accessibility of tenofovir/emtricitabine (Truvada) for first-line treatment for this population.

Immunogenicity and Safety of the Quadrivalent Human Papillomavirus Vaccine in HIV-1–Infected Women

BACKGROUND Women infected with human immunodeficiency virus (HIV) are disproportionately affected by human papillomavirus (HPV)-related anogenital disease, particularly with increased immunosuppression. AIDS Clinical Trials Group protocol A5240 was a trial of 319 HIV-infected women in the United States, Brazil, and South Africa to determine immunogenicity and safety of the quadrivalent HPV vaccine in 3 strata based on screening CD4 count: >350 (stratum A), 201-350 (stratum B), and ≤200 cells/µL (stratum C). METHODS Safety and serostatus of HPV types 6, 11, 16, and 18 were examined. HPV serological testing was performed using competitive Luminex immunoassay (HPV-4 cLIA). HPV type-specific seroconversion analysis was done for participants who were seronegative for the given type at baseline. RESULTS Median age of patients was 36 years; 11% were white, 56% black, and 31% Hispanic. Median CD4 count was 310 cells/µL, and 40% had undetectable HIV-1 load. No safety issues were identified. Seroconversion proportions among women at week 28 for HPV types 6, 11,16, and 18 were 96%, 98%, 99%, and 91%, respectively, for stratum A; 100%, 98%, 98%, and 85%, respectively, for stratum B, and 84%, 92%, 93%, and 75%, respectively, for stratum C. CONCLUSIONS The quadrivalent HPV vaccine targeted at types 6, 11, 16, and 18 was safe and immunogenic in HIV-infected women aged 13-45 years. Women with HIV RNA load >10 000 copies/mL and/or CD4 count <200 cells/µL had lower rates of seroconversion rates. Clinical Trials Registration. NCT00604175.

Validation of Cervical Cancer Screening Methods in HIV Positive Women from Johannesburg South Africa

Background HIV-infected women are at increased risk for developing cervical cancer. Women living in resource-limited countries are especially at risk due to poor access to cervical cancer screening and treatment. We evaluated three cervical cancer screening methods to detect cervical intraepithelial neoplasia grade 2 and above (CIN 2+) in HIV-infected women in South Africa; Pap smear, visual inspection with 5% acetic acid (VIA) and human papillomavirus detection (HPV). Methods HIV-infected women aged 18–65 were recruited in Johannesburg. A cross-sectional study evaluating three screening methods for the detection of the histologically-defined gold standard CIN-2 + was performed. Women were screened for cervical abnormalities with the Digene HC2 assay (HPV), Pap smear and VIA. VIA was performed by clinic nurses, digital photographs taken and then later reviewed by specialist physicians. The sensitivity, specificity and predictive valves for CIN-2 + were calculated using maximum likelihood estimators. Results 1,202 HIV-infected women participated, with a median age of 38 years and CD4 counts of 394 cells/mm3. One third of women had a high grade lesion on cytology. VIA and HPV were positive in 45% and 61% of women respectively. Estimated sensitivity/specificity for HPV, Pap smear and VIA for CIN 2+ was 92%/51.4%, 75.8%/83.4% and 65.4/68.5% (nurse reading), respectively. Sensitivities were similar, and specificities appeared significantly lower for the HPV test, cytology and VIA among women with CD4 counts ≤200 cells/mm3 as compared to CD4 counts >350 cells/mm3. Conclusions Although HPV was the most sensitive screening method for detecting CIN 2+, it was less specific than conventional cytology and VIA with digital imaging review. Screening programs may need to be individualized in context of the resources and capacity in each area.

Occult hepatitis B virus infection in patients with isolated core antibody and HIV co-infection in an urban clinic in Johannesburg, South Africa.

BACKGROUND The prevalence of HIV/hepatitis B virus (HBV) co-infection in South Africa ranges from 4.8% to 17% using the standard marker surface antigen (hepatitis B surface antigen, HBsAg) for chronic active HBV infection. However, sensitive molecular techniques for detecting HBV DNA in serum can detect occult HBV infection. We report the first observational prospective study of occult HBV infection in HIV-positive people in South Africa. METHODS Five hundred and two patients attending an urban hospital were screened for HBV using serological testing for HBsAg, core antibody (anti-HBc), and surface antibody (anti-HBs). DNA was analyzed using real-time quantitative PCR to determine the HBV viral load. RESULTS Of the 502 participants, 24 (4.8%) were HBsAg-positive and 53 (10.6%) were positive for anti-HBc alone. Of these 53, screening for occult disease was carried out in 43, of whom 38 (88.4%) were positive. The mean HBV viral load was 2.8 x 10(4) copies/ml (range 1 x 10(2) to 1 x 10(6) copies/ml). CONCLUSIONS Combining the participants with positive HBsAg and occult HBV DNA results, the prevalence of HBV increases from 4.8% (HBsAg alone) to 12.4%. While the clinical impact of occult HBV infection is unclear, consideration should be given to changing the guidelines to recommend dual HBV therapy for the treatment of co-infected patients in the developing world.

Incidence and progression of cervical lesions in women with HIV: A systematic global review

Global data on cervical lesion incidence and progression in HIV-positive women are essential for understanding the natural history of cervical neoplasia and informing screening policy. A systematic review was performed summarizing the incidence and progression of cervical lesions in HIV-positive women. Of 5882 HIV-positive women from 15 studies, incidence ranged from 4.9 to 21.1 cases per 100 woman-years for any cervical lesion and 0.4 to 8.8 cases per 100 woman-years for high-grade cervical lesions. HIV-positive women showed a median three-fold higher incidence of cervical lesions compared to HIV-negative women. Of 1099 HIV-positive women from 11 studies, progression from low- to high-grade lesions ranged from 1.2 to 26.2 cases per 100 woman-years. Both incidence and progression rates increased with lower CD4 counts. The effect of antiretroviral therapy on the natural history of cervical neoplasia remains unclear. HIV-positive women have higher incidence and progression of cervical neoplasia. Cervical cancer screening should be integrated into HIV treatment programmes.

Diverse and High Prevalence of Human Papillomavirus Associated with a Significant High Rate of Cervical Dysplasia in Human Immunodeficiency Virus–Infected Women in Johannesburg, South Africa

OBJECTIVE To evaluate the epidemiology of the human papillomavirus (HPV) type and correlate it with the Papanicolaou smears in human immunodeficiency virus-seropositive women in Johannesburg, South Africa. STUDY DESIGN In a cohort of 148 women, HPV DNA testing was performed with the Roche HPV genotyping test (Branchburg, New Jersey, U.S.A). Papanicolaou smears were performed by standard cytology utilizing 2001 Bethesda reporting guidelines. RESULTS The average age and CD4 count of the participants was 35 years and 255 cells per mm3, respectively. Fifty-four percent had abnormal Papanicolaou smears; 66% of the abnormal cytology was low grade changes, with 33% assessed as having high grade changes. HPV DNA was found in 95% of the 148 subjects assessed, with 83% having 1 or more HPV oncogenic types. Common oncogenic types were 16, 35, 53 and 18. When HPV results were stratified by CD4, there was a significant risk of an oncogenic HPV type in women with CD4 <200. Significant odds ratios for high grade lesions were seen in HPV types 16, 35, 51, 66, 69 and 73. CONCLUSION The results of HPV typing illustrate the diverse range of oncogenic HPV and high prevalence of oncogenic type. These results highlight the need for improved access to Papanicolaou smear screening for this population.

Highly active antiretroviral therapy and cervical dysplasia in HIV-positive women in South Africa

The risk of squamous intra‐epithelial lesions (SIL) is higher in HIV‐positive women. As these women begin to live longer due to highly active antiretroviral therapy (HAART), their risk of cervical cancer may increase. Few data exist regarding the effect of HAART on the incidence and progression of SIL in HIV‐positive African women. The aim of this study was to evaluate the effect of HAART on the incidence and progression of SIL in HIV‐positive women in South Africa.

Comparisons of anemia, thrombocytopenia, and neutropenia at initiation of HIV antiretroviral therapy in Africa, Asia, and the Americas

BACKGROUND Hematological abnormalities are common manifestations of advanced HIV-1 infection that could affect the outcomes of highly-active antiretroviral therapy (HAART). Although most HIV-1-infected individuals live in resource-constrained countries, there is little information about the frequency of hematological abnormalities such as anemia, neutropenia, and thrombocytopenia among individuals with advanced HIV-1 disease. METHODS This study compared the prevalence of pre-antiretroviral therapy hematological abnormalities among 1571 participants in a randomized trial of antiretroviral efficacy in Africa, Asia, South America, the Caribbean, and the USA. Potential covariates for anemia, neutropenia, and thrombocytopenia were identified in univariate analyses and evaluated in separate multivariable models for each hematological condition. RESULTS The frequencies of neutropenia (absolute neutrophil count ≤1.3×10⁹/l), anemia (hemoglobin ≤10g/dl), and thrombocytopenia (platelets ≤125×10⁹/l) at initiation of antiretroviral therapy were 14%, 12%, and 7%, respectively, and varied by country (p<0.0001 for each). In multivariable models, anemia was associated with gender, platelet count, and country; neutropenia was associated with CD4+ lymphocyte and platelet counts; and thrombocytopenia was associated with country, gender, and chronic hepatitis B infection. CONCLUSIONS Differences in the frequency of pretreatment hematological abnormalities could have important implications for the choice of antiretroviral regimen in resource-constrained settings.

Evaluation of Xpert MTB/RIF Versus AFB Smear and Culture to Identify Pulmonary Tuberculosis in Patients with Suspected Tuberculosis from Low and Higher Prevalence Settings

BACKGROUND The Xpert MTB/RIF (Xpert) assay is a rapid nucleic acid amplification test widely used in settings of high tuberculosis prevalence to detect tuberculosis as well asrpoBmutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower-prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation. METHODS Xpert was compared to 2 sputum samples, each evaluated with acid-fast bacilli (AFB) smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary tuberculosis from the United States, Brazil, and South Africa. RESULTS Of 992 participants enrolled with evaluable results, 22% had culture-confirmed tuberculosis. In 638 (64%) US participants, 1 Xpert result demonstrated sensitivity of 85.2% (96.7% in participants with AFB smear-positive [AFB(+)] sputum, 59.3% with AFB smear-negative [AFB(-)] sputum), specificity of 99.2%, negative predictive value (NPV) of 97.6%, and positive predictive value of 94.9%. Results did not differ between higher- and low-prevalence settings. A second Xpert assay increased overall sensitivity to 91.1% (100% if AFB(+), 71.4% if AFB(-)), with specificity of 98.9%. In US participants, a single negative Xpert result predicted the absence of AFB(+)/culture-positive tuberculosis with an NPV of 99.7%; NPV of 2 Xpert assays was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected tuberculosis DNA and mutations associated with rifampin resistance in 5 of 7 participants with rifampin-resistant, culture-positive tuberculosis. Specificity for rifampin resistance was 99.5% and NPV was 98.9%. CONCLUSIONS In the United States, Xpert testing performed comparably to 2 higher-tuberculosis-prevalence settings. These data support the use of Xpert in the initial evaluation of tuberculosis suspects and in algorithms assessing need for respiratory isolation.

Effect of trichomoniasis therapy on genital HIV viral burden among African women.

Background: Our objective was to test the hypothesis that treatment for trichomoniasis among HIV-infected women not taking antiretrovirals in South Africa would be associated with decreased HIV genital shedding. Methods: HIV-infected women presenting for routine HIV care were screened for trichomoniasis using self-collected vaginal swabs with a rapid point-of-care immunochromatographic antigen test. Women testing positive were offered enrollment into a prospective cohort study, if they had documented HIV infection, were aged 18 to 50 years, and were not receiving antiretroviral therapy. Recent use of postexposure prophylaxis or antibiotic therapy, active genital ulcers, or systemic illness were exclusion criteria. Cervical swabs were collected for gonococcal and chlamydial testing, and those testing positive were excluded. Women were treated with directly observed oral therapy with 2 g of oral metronidazole. A follow-up visit was scheduled 1 month after therapy, and partner letters were provided. Paired cervical wicks and plasma were collected for viral load measurement. Results: In all, 557 women were screened. Sixty tested positive for trichomoniasis, 10 subsequently met exclusion criteria, and 4 were lost to follow-up. Of 46 women evaluated at follow-up, 37 (80.4%) were cured. Plasma viral load was not significantly different after therapy (P = 0.93). Genital tract viral load decreased by 0.5 log10 (P < 0.01). The mean genital tract viral load (log10) decreased from 4.66 (<3.52–6.46) to 4.18 (<3.52–6.48) (P < 0.01) after therapy. Conclusions: Screening and treatment of vaginal trichomoniasis decrease genital shedding of HIV among South African women not receiving antiretrovirals at 1 month after therapy.