Insulin Resistance is Associated with Higher Plasma Viral Load Among HIV-Positive Adults Receiving Longer-Term (1 Year) Combination Antiretroviral Therapy (ART).

Background: As HIV-positive persons survive longer due to the success of combination antiretroviral therapy (ART) in decreasing mortality, the burden of non-communicable diseases including diabetes mellitus (DM) is anticipated to rise. HIV is characterized by systemic inflammations, markers of which decrease quickly following ART initiation, but typically do not completely normalize. Inflammation may be accompanied by insulin resistance (IR), and both are implicated in the pathogenesis of DM in HIV-positive individuals. Sub-Saharan Africa accounts for almost two-thirds of the global HIV burden but there are few reports of IR, DM and HIV in this region. We assessed the relationship between IR and viral suppression among HIV-positive adults in the Zambian national ART program. Methods: We conducted a cross-sectional survey evaluating HIV-positive adults that had received first line ART (usually TDF/FTC/EFV) for 12 months (± 3 months). Twenty clinics were sampled systematically based on the random starting-point, sampling interval and cumulative population size. Eligible patients had plasma viral load (VL), fasting insulin, and glucose performed. Insulin resistance was determined using Homeostatic model assessment (HOMA). We determined proportions for each outcome using linearized standard error 95% confidence intervals and summary estimates. Viral suppression was defined according to the detection threshold of<20 copies/mL and treatment failure was defined as VL>1,000 copies/mL. Results: Of 473 patients enrolled, 46.8% were male and 53.2% were female. 142 (30%) [95% CI: 0.26-0.34] had IR. Among those with IR, 55 (38.7%) were male whereas 87 (61.3%) were female (p value=0.104). 19% of individuals with IR had treatment failure compared to 5.7% without IR (p value<0.0001). 427 (90.3%) participants had treatment success (VL<1,000 copies/mL), and this was associated with a lower likelihood of IR (odds ratio (OR)=0.26 [0.14, 0.48], p value<0.0001). In addition, a significantly lower proportion of patients with IR were virologically suppressed at one-year compared to individuals without IR, 58% [0.54-0.70] versus 70% [0.65-0.75], respectively (p value=0.042). Conclusion: In Zambian adults on ART for a year, the development of insulin resistance was strongly associated with suboptimal HIV outcomes, specifically non-viral suppression and treatment failure. Further investigations are warranted to determine if this positive association between IR and VL is causally related, and if so in which direction.

HLA-G 14 bp deletion/insertion polymorphism and mother-to-child transmission of HIV.

The human leukocyte antigen HLA-G, highly expressed at the maternal-fetal interface, has a pivotal role in mediating immune tolerance. In this study we investigated the influence of HLA-G 14 bp insertion polymorphism in human immunodeficiency virus (HIV)-1 mother-to-child HIV-1 transmission. The 14 bp insertion polymorphism was analyzed among 99 HIV-1 positive mothers and 329 infants born to HIV-positive mothers in Zambia, among whom vertical transmission status and timing had been determined. HLA-G 14 bp insertion polymorphism was detected using a custom TaqMan single nucleotide polymorphisms (SNPs) genotyping assay. Logistic regression was conducted to examine the associations between HLA-G alleles and the risk of HIV transmission. The 14 bp insertion allele was more frequent in HIV exposed-uninfected (EU) infants than in infected infants, and was associated with reduced risk of both in utero (IU) and intrapartum (IP) HIV transmission, after adjusting for maternal cluster of differentiation 4 (CD4) cell count and plasma viral load. Maternal HLA-G 14 bp insertion genotype and HLA-G concordance between mother and child were not associated with the risk of perinatal HIV transmission. The presence of the 14 bp insertion associates with protection toward IU and IP HIV infection in children from Zambia, suggesting that HLA-G could be involved in the vertical transmission of HIV.

[Determinants of low birth weight among newborns to HIV-infected mothers not eligible for antiretroviral treatment in Africa]. / Déterminants du faible poids de naissance chez des enfants nés de mères séropositives pour le VIH, non éligibles au traitement antirétroviral, en Afrique.

BACKGROUND: Low birth weight (LBW) increases the risk of infant death, but little is known about its rate and determinants among babies born to HIV-infected mothers in sub-Saharan Africa. METHODS: This study was conducted in South Africa, Burkina Faso, Uganda and Zambia, during the recruitment process of the PROMISE-PEP (ANRS 12174) clinical trial. The study sample included 1196 subjects screened between August 2009 and December 2011, respectively 254 in South Africa, 221 in Burkina Faso, 197 in Uganda and 524 in Zambia, all ineligible for antiretroviral therapy. Data were collected during ANRS12174 clinical trial antenatal and postnatal screening visits, and during an inclusion visit for completion of an electronic case report form (eCRF). RESULTS: The mean (±SD) age of mothers was 27±5years and their mean CD4 count was 576±195cells/µL. Most mothers lived in a couple (78.7%), had no employment (72.3%) and had a good level of education (74% had gone to school). Male newborns predominated (51.7%). The mean birth weight was 3043g±435g, and 7.8% ([95%CI: 6.3%-9.3%]) of newborns weighed less than 2500g. In univariate analyses, being married or cohabiting, body mass index, WHO HIV disease stage II, female newborn and low gestational age were associated with risk of LBW. In multivariate regression model, low gestational age (aOR=3.74, P<0.0001) and female newborn (aOR=1.63, P=0.04) were significantly associated with LBW. CONCLUSION: The risk factors for LBW found in HIV-infected women ineligible for antiretroviral therapy were the same as in the general population. There was no evidence of additional risk factors associated with HIV infection.

Strategies for nevirapine initiation in HIV-infected children taking pediatric fixed-dose combination "baby pills" in Zambia: a randomized controlled trial.

BACKGROUND: Fixed-dose combination scored dispersible stavudine, lamivudine, and nevirapine minitablets (Triomune Baby and Junior; Cipla Ltd) are simpler and cheaper than liquid formulations and have correct dose ratios for human immunodeficiency virus-infected children. However, they cannot be used for dose escalation (DE) of nevirapine. METHODS: Children were randomized to initiate antiretroviral therapy with full-dose (FD) nevirapine (Triomune Baby or Junior in the morning and evening) versus DE (half-dose nevirapine for 14 days [Triomune in the morning and stavudine-lamivudine {Lamivir-S} in the evening], then FD), in accordance with World Health Organization weight-band dosing tables. The primary end point was nevirapine-related clinical or laboratory grade 3 or 4 adverse events (AEs). RESULTS: In total, 211 children (median [interquartile range {IQR}] age, 5 [ 2-9 ] years; median [IQR] CD4 cell percentage, 13% [8%-18%]) were enrolled and followed up for a median (IQR) of 92 (68-116) weeks. There were 31 grade 3 or 4 AEs that were definitely/probably or uncertainly related to nevirapine in the FD group (18.0 per 100 child-years), compared with 29 in the DE group (16.5 per 100 child-years) (incidence rate ratio, 1.09; 95% confidence interval, 0.63–1.87; P = .74). All were asymptomatic; 11 versus 3 were single grade 3 or 4 elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, all of which resolved without a change in nevirapine dose or interruption. Thirteen (12%) FD versus 2 (2%) DE children had grade 1 (2 in FD) or grade 2 (11 in FD and 2 in DE) rashes. Three (2 in FD and 1 in DE) substituted efavirenz, 3 (FD) continued FD nevirapine, and 9 (8 in FD and 1 in DE) temporarily interrupted nevirapine, followed by successful DE. Predictors of nevirapine rash were older age (P = .003) and higher CD4 cell count for age (P = .03). Twenty-two children died (12 in FD and 10 in DE), 1 FD and 5 DE children at <4 weeks; none were considered to be drug related by independent review. CONCLUSIONS: Rash was more frequent with FD nevirapine, but 88% had no clinical toxicity; elevated AST or ALT levels were transient and resolved spontaneously, suggesting that routine laboratory monitoring has limited value. Dual pediatric stavudine-lamivudine minitablets are preferred for safe and simple DE; if unavailable, initiating FD Triomune requires timely review for rash, which could be managed by temporary reduction to half-dose Triomune or efavirenz substitution. TRIAL REGISTRATION: Current Controlled Trials identifier: ISRCTN31084535 .

Factors associated with HIV prevalence in a pre-partum cohort of Zambian women.

An ongoing study of mother-to-child human herpes virus-8 (HHV-8) transmission in Zambian women (n = 3160) allowed us to examine the association of medical injections with HIV serostatus while simultaneously accounting for other factors known to be correlated with HIV prevalence. Multi-method data collection included structured interviews, medical record abstraction, clinical examinations, and biological measures. Medically administered intramuscular or intravenous injections in the past five years (but not blood transfusions) were overwhelmingly correlated with HIV prevalence, exceeding the contribution of sexual behaviours in a multivariable logistic regression. Statistically significant associations with HIV also were found for some demographic variables, sexual behaviours, alcohol use, and sexually transmitted diseases (STD). The results confirmed that iatrogenic needle exposure, sexual behaviour, demographic factors, substance use, and STD history are all implicated in Zambian women's HIV+ status. However, the disproportionate association of medical injection history with HIV highlights the need to investigate further and prospectively the role of health-care injection in sub-Saharan Africa's HIV epidemic.

Molecularly cloned SHIV-1157ipd3N4: a highly replication- competent, mucosally transmissible R5 simian-human immunodeficiency virus encoding HIV clade C Env.

Human immunodeficiency virus type 1 (HIV-1) clade C causes >50% of all HIV infections worldwide, and an estimated 90% of all transmissions occur mucosally with R5 strains. A pathogenic R5 simian-human immunodeficiency virus (SHIV) encoding HIV clade C env is highly desirable to evaluate candidate AIDS vaccines in nonhuman primates. To this end, we generated SHIV-1157i, a molecular clone from a Zambian infant isolate that carries HIV clade C env. SHIV-1157i was adapted by serial passage in five monkeys, three of which developed peripheral CD4(+) T-cell depletion. After the first inoculated monkey developed AIDS at week 137 postinoculation, transfer of its infected blood to a naïve animal induced memory T-cell depletion and thrombocytopenia within 3 months in the recipient. In parallel, genomic DNA from the blood donor was amplified to generate the late proviral clone SHIV-1157ipd3. To increase the replicative capacity of SHIV-1157ipd3, an extra NF-kappaB binding site was engineered into its 3' long terminal repeat, giving rise to SHIV-1157ipd3N4. This virus was exclusively R5 tropic and replicated more potently in rhesus peripheral blood mononuclear cells than SHIV-1157ipd3 in the presence of tumor necrosis factor alpha. Rhesus macaques of Indian and Chinese origin were next inoculated intrarectally with SHIV-1157ipd3N4; this virus replicated vigorously in both sets of monkeys. We conclude that SHIV-1157ipd3N4 is a highly replication-competent, mucosally transmissible R5 SHIV that represents a valuable tool to test candidate AIDS vaccines targeting HIV-1 clade C Env.

Epidemiological characteristics of human herpesvirus-8 infection in a large population of antenatal women in Zambia.

Comprehensive data describing epidemiological characteristics of the human herpesvirus-8 or Kaposi's sarcoma-associated herpesvirus (HHV-8 or KSHV) infection among pregnant women in a central sub-Saharan Africa are not available. This study determined virus prevalence estimates and the risk factors associated with HHV-8 infection. Cross-sectional, enrollment visit data were analyzed from a prospective cohort study of perinatal transmission of HHV-8 in Lusaka, Zambia. Exposure data were obtained via structured interview, physical examination, medical chart review, and laboratory testing. Among 3,160 antenatal women serologically screened for HHV-8 between September 1998 and October 2000, 40.2% were seropositive. The HHV-8 positive women were more likely to be co-infected with HIV-1 than those who were HHV-8 negative (34% vs. 26%; P < 0.0001). Of 154 variables evaluated by logistic regression analyses, only three risk factors, have emerged as independent predictors of HHV-8 positive serology: diagnosis of genital warts, HIV-1 co-infection and primary education. The association of HHV-8 infection with genital warts and HIV-1 co-infection suggests heterosexual transmission of HHV-8. HIV-1 infection may also act as a marker for particular behaviors, which could be sexual in nature, that are associated with both HIV-1 and HHV-8 transmission. Since HHV-8 facilitates development of AIDS-related Kaposi's sarcoma (KS), the results of this study could be utilized to identify specific population groups of pregnant women who are at increased risk for this disease.

Vertical transmission of Kaposi's sarcoma-associated herpesvirus.

Little is presently known about the specific routes of transmission of Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8). To investigate whether this agent might be transmitted vertically from mother to infant, we conducted a study on 89 KSHV seropositive mothers and their newborn infants. Thirteen mothers (14.6%) had KSHV DNA detected in their peripheral blood mononuclear cells (PBMC). Two of 89 samples drawn at birth from infants born to KSHV seropositive mothers had KSHV DNA detectable within their PBMC. These findings suggest that KSHV can be transmitted perinatally, but infrequently. Other routes of transmission such as horizontal transmission remain the most likely means of KSHV transmission.

Potent neutralization of primary human immunodeficiency virus clade C isolates with a synergistic combination of human monoclonal antibodies raised against clade B.

OBJECTIVES: We investigated the ability of several human neutralizing monoclonal antibodies (mAbs), originally raised against human immunodeficiency virus (HIV) clade B isolates, to neutralize primary clade C isolates as single agents and in combination. STUDY DESIGN/METHODS: HIV clade C isolates from five different countries were tested for susceptibility to neutralization by anti-clade B mAbs in human peripheral blood mononuclear cells. Monoclonal antibody combinations were evaluated for possible synergy. RESULTS: All 20 primary HIV clade C isolates could be neutralized 97.5% to 100% by a quadruple combination of mAbs IgG1b12, 2G12, 2F5, and 4E10. These mAbs recognized conserved epitopes and were highly synergistic, resulting in strong cross-clade neutralization. CONCLUSIONS: In our previous experiment, a synergistic combination of human neutralizing mAbs protected all macaque neonates against oral challenge with a simian-human immunodeficiency virus encoding HIV env. Together, our data suggest that passive immunization with currently available anti-clade B mAbs could play a role in preventing HIV clade C transmission through breastfeeding.

Seroprevalence of human herpesvirus 8 among Zambian women of childbearing age without Kaposi's sarcoma (KS) and mother-child pairs with KS.

The seroprevalence of human herpesvirus 8 (HHV-8) among a group of Zambian women of reproductive age and among mother-child pairs in which either one of them has Kaposi's sarcoma (KS) was determined. A cross-sectional group of 378 pregnant women was randomly recruited into the study, and 183 (48.4%) had HHV-8 antibodies. Among the human immunodeficiency virus (HIV)-1-infected women, 51.1% were HHV-8-seropositive, whereas of HIV-1-negative women, 47.3% were HHV-8-seropositive. In addition, 21 women index patients with KS and 5 young children index patients with KS were studied. All children with KS had mothers who were HHV-8-seropositive, while not all children whose mothers had KS were infected with HHV-8. Our study suggests that there is a high HHV-8 seroprevalence among Zambian women, and the rate is almost the same in HIV-1-positive and -negative women. This high seroprevalence may be a contributing factor toward the increased frequency of KS in this population.