Effect of Maternal Immunization With 10-Valent Pneumococcus Conjugate Vaccine (PCV-10), 23-Valent Pneumococcus Polysaccharide Vaccine, or Placebo on the Immunogenicity of PCV-10 in Human Immunodeficiency Virus-Exposed Uninfected Infants: A Randomized Clinical Trial.

BACKGROUND: The effect of pneumococcal vaccination of mothers with human immunodeficiency virus (HIV) on infant responses to childhood vaccination has not been studied. We compared the immunogenicity of 10-valent pneumococcus conjugate vaccine (PCV-10) in HIV-exposed uninfected infants born to mothers who received PCV-10, 23-valent pneumococcus polysaccharide vaccine (PPV-23), or placebo during pregnancy. METHODS: Antibody levels against 7 serotypes were measured at birth, before the first and second doses of PCV-10m and after completion of the 2-dose regimen in 347 infants, including 112 born to mothers who received PPV-23, 112 who received PCV-10, and 119 who received placebo during pregnancy. Seroprotection was defined by antibody levels ≥0.35 µg/mL. RESULTS: At birth and at 8 weeks of life, antibody levels were similar in infants born to PCV-10 or PPV-23 recipients and higher than in those born to placebo recipient. After the last dose of PCV-10, infants in the maternal PCV-10 group had significantly lower antibody levels against 5 serotypes than those in the maternal PPV-23 group and against 3 serotypes than those in the maternal placebo group, and they did not have higher antibody levels against any serotype. The seroprotection rate against 7 serotypes was 50% in infants in the maternal PCV-10 group, compared with 71% in both of the maternal PPV-23 and placebo groups (P < .001). CONCLUSIONS: Administration of PCV-10 during pregnancy was associated with decreased antibody responses to PCV-10 and seroprotection rates in infants. Considering that PCV-10 and PPV-23 had similar immunogenicity in pregnant women with HIV and that administration of PPV-23 did not affect the immunogenicity of PCV-10 in infants, PPV-23 in pregnancy may be preferred over PCV-10.

Low prevalence of human gammaherpesvirus 8 (HHV-8) infection among HIV-infected pregnant women in Rio De Janeiro, Brazil.

Pregnant women coinfected with the human immunodeficiency virus (HIV) and human gammaherpesvirus 8 (HHV-8) are at higher risk of Kaposi's sarcoma development, increased viral load, and vertical transmission of these viruses. A total of 131 pregnant women infected with HIV were examined for antibodies against HHV-8 latency-associated nuclear antigen (LANA) and lytic antigens using immunofluorescence assays. The presence of HHV-8 DNA was confirmed using real-time polymerase chain reaction (qPCR) and nested PCR. Overall, 0.8% (1/131) of the patients contained antibodies to HHV-8 LANA and lytic antigens, and no HHV-8 DNA was detected. This study, including a small population of HIV-infected pregnant women in Brazil, indicates a low prevalence of HHV-8 seropositivity and absence of active infection in this group. However, a potential role of HHV-8 in the increased transmission and pathogenic activity of HIV in pregnant women is suggested. Attention should be given to the emergence of HHV-8 infection in this population group in order to avoid comorbidities and transmission of HIV.

Sexually transmitted infections among HIV-infected and HIV-uninfected women in the Tapajós region, Amazon, Brazil: Self-collected vs. clinician-collected samples.

The anogenital prevalence of sexually transmitted infections (STIs) and the use of cervico-vaginal self-collected vs. clinician-collected samples were evaluated for the diagnosis of human immunodeficiency virus (HIV)-infected and HIV-uninfected women in the Tapajós region, Amazon, Brazil. We recruited 153 women for a cross-sectional study (112 HIV-uninfected and 41 HIV-infected) who sought health services. Anal and cervical scrapings and cervico-vaginal self-collection samples were collected. Real-time polymerase chain reaction methods were used for Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Mycoplasma genitalium. A syphilis test was also performed. Risk factors for STIs were identified by multivariate analysis. The overall prevalence of STIs was 30.4% (34/112) in HIV-uninfected women and 24.4% (10/41) in HIV-infected women. Anogenital Chlamydia trachomatis infection was the most prevalent in both groups of women (20.5% vs 19.5%). There was significant agreement for each STI between self-collected and clinician-collected samples: 91.7%, kappa 0.67, 95% confidence interval (CI) 0.49-0.85 for Chlamydia trachomatis; 99.2%, kappa 0.85, 95% CI 0.57-1.00 for Neisseria gonorrhoeae; 97.7%, kappa 0.39, 95% CI -0.16-0.94 for Trichomonas vaginalis; and 94.7%, kappa 0.51, 95% CI 0.20-0.82 for Mycoplasma genitalium. Women with human papillomavirus had coinfection or multiple infections with other STIs. Risk factors for STIs were being ≤ 25 years old, being employed or a student, reporting a history of STI and having a positive HPV test. A high prevalence of STIs in women in the Tapajós region was found. Cervico-vaginal self-collection is a useful tool for STI screening and can be used in prevention control programs in low-resource settings, such as in northern Brazil.

Phylogenetic Methods Inconsistently Predict the Direction of HIV Transmission Among Heterosexual Pairs in the HPTN 052 Cohort.

BACKGROUND: We evaluated use of phylogenetic methods to predict the direction of human immunodeficiency virus (HIV) transmission. METHODS: For 33 pairs of HIV-infected patients (hereafter, "index patients") and their partners who acquired genetically linked HIV infection during the study, samples were collected from partners and index patients close to the time when the partner seroconverted (hereafter, "SC samples"); for 31 pairs, samples collected from the index patient at an earlier time point (hereafter, "early index samples") were also available. Phylogenies were inferred using env next-generation sequences (1 tree per pair/subtype). The direction of transmission (DoT) predicted from each tree was classified as correct or incorrect on the basis of which sequences (those from the index patient or the partner) were closest to the root. DoT was also assessed using maximum parsimony to infer ancestral node states for 100 bootstrap trees. RESULTS: DoT was predicted correctly for both single-pair and subtype-specific trees in 22 pairs (67%) by using SC samples and in 23 pairs (74%) by using early index samples. DoT was predicted incorrectly for 4 pairs (15%) by using SC or early index samples. In the bootstrap analysis, DoT was predicted correctly for 18 pairs (55%) by using SC samples and for 24 pairs (73%) by using early index samples. DoT was predicted incorrectly for 7 pairs (21%) by using SC samples and for 4 pairs (13%) by using early index samples. CONCLUSIONS: Phylogenetic methods based solely on the tree topology of HIV env sequences, particularly without consideration of phylogenetic uncertainty, may be insufficient for determining DoT.

Cervico-vaginal self-collection in HIV-infected and uninfected women from Tapajós region, Amazon, Brazil: High acceptability, hrHPV diversity and risk factors.

OBJECTIVE: We evaluated acceptability of cervico-vaginal self-collection (CVSC) and prevalence of human papillomavirus (HPV) in Human immunodeficiency virus (HIV)-infected and HIV-uninfected women living in the Tapajós region, Amazon, Brazil. METHODS: Cross-sectional study recruited 153 non-indigenous women (HIV-uninfected, n = 112 and HIV-infected, n = 41) who voluntarily sought assistance in health services. Peripheral blood for HIV screening and cervical scraping (CS) for HPV detection were collected. Women who accepted to perform CVSC received instructions and individual collection kits. Risk factors for high-risk HPV genotypes (hrHPV) were identified by uni- and multivariate analyses. RESULTS: The overall acceptability of CVSC was 87%. Only HIV-infected women had cytological abnormalities (12.2%). Prevalence of any HPV and hrHPV infection was 42.9% and 47.9% for HIV-uninfected and 97.6% and 77.5% for HIV-infected women, respectively. There was significant agreement in the detection of HPV (88%, 0.76, 95% confidence interval [CI], 0.65-0.87) and hrHPV (79.7%, 0.56, 95% CI, 0.41-0.71) between self-collected and clinician-collected samples. The most prevalent hrHPV types were HPV16 and HPV18 in HIV-uninfected and HPV16, HPV51 and HPV59 in HIV-infected women. HIV-infected women with hrHPV infection had multiple hrHPV infections (p = 0.005) and lower CD4 count (p = 0.018). Risk factors for hrHPV infection included being HIV-infected and having five or more sexual partners. CONCLUSIONS: CVSC had high acceptability and high prevalence of hrHPV types in women living in the Tapajós region, Amazon, Brazil.

HIV Drug Resistance in Adults Receiving Early vs. Delayed Antiretroviral Therapy: HPTN 052.

INTRODUCTION: We evaluated HIV drug resistance in adults who received early vs. delayed antiretroviral therapy (ART) in a multinational trial [HIV Prevention Trials Network (HPTN) 052, enrollment 2005-2010]. In HPTN 052, 1763 index participants were randomized to start ART at a CD4 cell count of 350-550 cells/mm (early ART arm) or <250 cells/mm (delayed ART arm). In May 2011, interim study results showed benefit of early ART, and all participants were offered ART regardless of CD4 cell count; the study ended in 2015. METHODS: Virologic failure was defined as 2 consecutive viral loads >1000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pretreatment (baseline) and failure samples from participants with virologic failure. RESULTS: HIV genotyping results were obtained for 211/249 participants (128 early ART arm and 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared with delayed ART arm, P = 0.06; compared with delayed ART arm with ART initiation before May 2011, P = 0.032). In multivariate analysis, higher baseline viral load (P = 0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared with other regimens, P = 0.024) were independently associated with higher risk of new resistance at failure. CONCLUSIONS: In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load.

Association of HIV diversity and virologic outcomes in early antiretroviral treatment: HPTN 052.

Higher HIV diversity has been associated with virologic outcomes in children on antiretroviral treatment (ART). We examined the association of HIV diversity with virologic outcomes in adults from the HPTN 052 trial who initiated ART at CD4 cell counts of 350-550 cells/mm3. A high resolution melting (HRM) assay was used to analyze baseline (pre-treatment) HIV diversity in six regions in the HIV genome (two in gag, one in pol, and three in env) from 95 participants who failed ART. We analyzed the association of HIV diversity in each genomic region with baseline (pre-treatment) factors and three clinical outcomes: time to virologic suppression after ART initiation, time to ART failure, and emergence of HIV drug resistance at ART failure. After correcting for multiple comparisons, we did not find any association of baseline HIV diversity with demographic, laboratory, or clinical characteristics. For the 18 analyses performed for clinical outcomes evaluated, there was only one significant association: higher baseline HIV diversity in one of the three HIV env regions was associated with longer time to ART failure (p = 0.008). The HRM diversity assay may be useful in future studies exploring the relationship between HIV diversity and clinical outcomes in individuals with HIV infection.

Brief Report: HIV Drug Resistance in Adults Failing Early Antiretroviral Treatment: Results From the HIV Prevention Trials Network 052 Trial.

Early initiation of antiretroviral treatment (ART) reduces HIV transmission and has health benefits. HIV drug resistance can limit treatment options and compromise use of ART for HIV prevention. We evaluated drug resistance in 85 participants in the HIV Prevention Trials Network 052 trial who started ART at CD4 counts of 350-550 cells per cubic millimeter and failed ART by May 2011; 8.2% had baseline resistance and 35.3% had resistance at ART failure. High baseline viral load and less education were associated with emergence of resistance at ART failure. Resistance at ART failure was observed in 7 of 8 (87.5%) participants who started ART at lower CD4 cell counts.

Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial.

BACKGROUND: Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. METHODS: The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. FINDINGS: 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per µL in patients assigned to the early treatment group and 428 (357-522) cells per µL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per µL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. INTERPRETATION: Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. FUNDING: US National Institute of Allergy and Infectious Diseases.

Mother-to-Child Transmission of Hepatitis C Virus (HCV) Among HIV/HCV-Coinfected Women.

BACKGROUND: Maternal human immunodeficiency virus (HIV) coinfection has been associated with increased hepatitis C virus (HCV) mother-to-child transmission (MTCT). We hypothesized that HCV/HIV-coinfected women with well-controlled HIV disease would not have increased HCV MTCT. METHODS: The NISDI Perinatal and LILAC cohorts enrolled HIV-infected pregnant women and their infants in Latin America and the Caribbean. This substudy evaluated the HCV infection status of mothers at participating sites and their live born, singleton infants who had a 6-month postnatal visit by December 31, 2008. Mothers who were anti-HCV-positive, or who had CD4 counts (cells/mm(3)) <200 with detectable HCV RNA, were considered HCV-infected. All HCV-infected women were tested for HCV RNA. Infants with HCV RNA were considered HCV-infected. RESULTS: Of 1042 enrolled women, 739 (71%) mother-infant pairs met the inclusion criteria. Of the 739 women, 67 (9%) were anti-HCV-positive and 672 anti-HCV-negative [68 (10%) with CD4 counts <200; of these, 3 (4.4%) were HCV RNA-positive]. Therefore, our study population comprised 70 HCV-infected (47 with HCV RNA) and 669 HCV-uninfected women (and their infants). Factors associated with maternal HCV infection included unemployment (odds ratio [OR] = 2.58); tobacco (OR = 1.73) or marijuana (OR = 3.88) use during pregnancy; enrollment HIV viral load ([VL] copies/mL) ≥10 000 (OR = 2.27); HIV clinical disease stage C (OR = 2.12); and abnormal alanine aminotransferase (OR = 4.24) or aspartate aminotransferase (OR = 11.98). Four of 47 infants (8.5%) born to HCV-viremic women were HCV-infected, and all 4 mothers had HIV VL <1000 at hospital discharge after delivery. CONCLUSIONS: HCV MTCT among HIV/HCV-coinfected women with well-controlled HIV disease may be lower than reported in other coinfected populations. Studies with longer infant follow-up are needed.

Antiretroviral adherence during pregnancy and postpartum in Latin America.

Adherence to antiretrovirals by pregnant women (and postpartum women if breastfeeding) is crucial to effectively decrease maternal viral load and decrease the risk of mother-to-child transmission of HIV. Our objectives were to describe self-reported adherence to antiretrovirals during the antepartum (after 22 weeks of pregnancy) and postpartum periods (6-12 weeks and 6 months), and identify predictors of adherence among HIV-infected women enrolled and followed in a prospective cohort study from June 2008 to June 2010 at multiple sites in Latin America. Adherence was evaluated using the number of missed and expected doses during the 3 days before the study visit. At the pre-delivery visit, 340 of 376 women (90%) reported perfect adherence. This rate significantly decreased by 6-12 weeks (171/214 [80%]) and 6 months postpartum (163/199 [82%], p<0.01). The odds for less than perfect adherence at the pre-delivery visit was significantly higher for pregnant women with current tobacco use (odds ratio [OR]=2.9, 95% confidence interval [CI]: 1.46-6.14; p=0.0029). At 6-12 weeks postpartum, the probability of non-perfect adherence increased by 6% for each 1 year increase in age (OR=1.06, 95% CI: 1.00-1.12, p=0.0497). At 6 months postpartum, the odds of nonperfect adherence was higher for those who were currently using alcohol (OR=3.04, 95% CI: 1.34-6.90; p=0.0079). Although a self-report measure of adherence based on only 3 days may lead to overestimation of actual adherence over time, women with perfect adherence had lower viral loads and higher CD4 counts. Adherence to antiretrovirals decreased significantly postpartum. Interventions should target women at high risk for lower adherence during pregnancy and postpartum, including tobacco and alcohol users.

Anti-human immunodeficiency virus type 1 humoral immune response and highly active antiretroviral treatment

Highly active antiretroviral treatment (HAART) of human immunodeficiency type 1 (HIV-1) infection is very effective in controlling infection, but elimination of viral infection has not been achieved as yet, and upon treatment interruption an immediate rebound of viremia is observed. A combination of HAART with an immune stimulation might allow treatment interruption without this rebounding viremia, as the very low viremias observed with successful HAART may be insufficient to permit maintenance of a specific anti-HIV-1 immune response. The objective of this study was to compare the humoral immune response of individuals undergoing successful HAART (NF=no failure) with that of individuals with evidence of failure of therapy (FT) and to verify if the viremia peaks observed in individuals with therapy failure would act as a specific stimulus for the humoral anti-HIV-1 immune response. Antibodies binding to gp120 V3 genotype consensus peptides were more frequently observed for FT, mainly against peptides corresponding to sequences of genotypes prevalent in the Rio de Janeiro city area, B and F. HIV-1 neutralization of HIV-1 IIIB and of four primary isolates from Rio de Janeiro was less frequently observed for plasma from the NF than the FT group, but this difference was more expressive when plasma from individuals with detectable viremia were compared to that of individuals with undetectable viral loads in the year before sample collection. Although statistically significant differences were observed only in some specific comparisons, the study indicates that presence of detectable viremia may contribute to the maintenance of a specific anti-HIV-1 humoral immune response.