Mother-to-child transmission of HIV-1 in the era prior to the availability of combination antiretroviral therapy: the role of drugs of abuse

Since the use of combination antiretroviral therapy (HAART) to treat pregnant women, the rate of mother-to-child transmission (MTCT) of HIV in the United States has dropped dramatically to less than 2%. With this, the principal determinants of the risk of transmission are the maternal viral load and her use of antiretroviral therapy (ART). However, in the pre-HAART era, the MTCT ranged from 12 to 45% and was influenced by a variety of risk factors for transmission including no ART during pregnancy or delivery, advanced maternal HIV infection (high viral load, low CD4 count, and AIDS diagnosis), prolonged rupture of membranes, first-born of twins, prematurity/low birth weight, chorioamnionitis, vaginal delivery or non-elective Cesarean section, and maternal drug use. Several studies in the pre-HAART era found maternal illicit drug use to be an independent predictor of MTCT. Reasons for this association may be both behavioral and biological. Drug use is associated with poor adherence to ART and medical care. Opioids enhance infection of macrophages by HIV.     

Drugs of abuse and HIV infection/replication: implications for mother-fetus transmission

Human immunodeficiency virus (HIV) infection and progression of acquired immunodeficiency syndrome (AIDS) can be modulated by a number of cofactors, including drugs of abuse. Opioids, cocaine, cannabinoids, methamphetamine (METH), alcohol, and other substances of abuse have been implicated as risk factors for HIV infection, as they all have the potential to compromise host immunity and facilitate viral replication. Although epidemiologic evidence regarding the impact of drugs of abuse on HIV disease progression is mixed, in vitro studies as well as studies using in vivo animal models have indicated that drugs of abuse have the ability to enhance HIV infection/replication. Drugs of abuse may also be a risk factor for perinatal transmission of HIV. Because high levels of viral load in maternal blood are associated with increased risk of HIV vertical transmission, it is likely that drugs of abuse play an important role in promoting mother-fetus transmission. Furthermore, because the neonatal immune system differs qualitatively from the adult system, it is possible that maternal exposure to drugs of abuse would exacerbate neonatal immunity defects, facilitating HIV infection of neonate immune cells and promoting HIV vertical transmission. The availability and use of antiretroviral therapy for women infected with HIV increase, there is an increasing interest in determining the impact of drug abuse on efficacy of AIDS Clinical Trials Group (ACTG)-standardized treatment regimens for woman infected with HIV in the context of HIV vertical transmission.     

Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals

Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV(+) pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects.     

Mother-to-child transmission of HIV in Botswana: an ethical perspective on mandatory testing

Mother-to-child transmission (MTCT) of HIV represents a particularly dramatic aspect of the HIV epidemic with an estimated 600,000 newborns infected yearly, 90% of them living in sub-Saharan Africa. Since the beginning of the HIV epidemic, an estimated 5.1 million children worldwide have been infected with HIV. MTCT is responsible for 90% of these infections. Two-thirds of the MTCT are believed to occur during pregnancy and delivery, and about one-third through breastfeeding. As the number of women of child bearing age infected with HIV rises, so does the number of infected children. It is apparent that voluntary testing in Botswana has made some valuable inroads in decreasing perinatal HIV transmission, but the statistics showing the increased rate of HIV infection among women 15-24 years of age are not very promising. After reviewing all the pertinent scientific data it is clear that mandatory HIV testing of all pregnant women in conjunction with the implementation of a full package of interventions would save thousands of lives -- mothers, newborns and others who could be infected as a result of these women not being aware of their HIV status. If the protection and preservation of human life is a priority in Botswana, then it is time to allow for mandatory HIV testing of all pregnant women, before it is too late for those who are the most vulnerable. To do less would be medically inappropriate and ethically irresponsible.     

Mutations that confer resistance to broadly-neutralizing antibodies define HIV-1 variants of transmitting mothers from that of non-transmitting mothers

Despite considerable reduction of mother-to-child transmission (MTCT) of HIV through use of maternal and infant antiretroviral therapy (ART), over 150,000 infants continue to become infected with HIV annually, falling far short of the World Health Organization goal of reaching <20,000 annual pediatric HIV cases worldwide by 2020. Prior to the widespread use of ART in the setting of pregnancy, over half of infants born to HIV-infected mothers were protected against HIV acquisition. Yet, the role of maternal immune factors in this protection against vertical transmission is still unclear, hampering the development of synergistic strategies to further reduce MTCT. It has been established that infant transmitted/founder (T/F) viruses are often resistant to maternal plasma, yet it is unknown if the neutralization resistance profile of circulating viruses predicts the maternal risk of transmission to her infant. In this study, we amplified HIV-1 envelope genes (env) by single genome amplification and produced representative Env variants from plasma of 19 non-transmitting mothers from the U.S. Women Infant Transmission Study (WITS), enrolled in the pre-ART era. Maternal HIV Env variants from non-transmitting mothers had similar sensitivity to autologous plasma as observed for non-transmitting variants from transmitting mothers. In contrast, infant variants were on average 30% less sensitive to paired plasma neutralization compared to non-transmitted maternal variants from both transmitting and non-transmitting mothers (p = 0.015). Importantly, a signature sequence analysis revealed that motifs enriched in env sequences from transmitting mothers were associated with broadly neutralizing antibody (bnAb) resistance. Altogether, our findings suggest that circulating maternal virus resistance to bnAb-mediated neutralization, but not autologous plasma neutralization, near the time of delivery, predicts increased MTCT risk. These results caution that enhancement of maternal plasma neutralization through passive or active vaccination during pregnancy may potentially drive the evolution of variants fit for vertical transmission.     

Mother-to-child transmission of HIV-1 in sub-Saharan Africa: past, present and future challenges

HIV prevalence continues to be high among women of reproductive age in sub-Saharan Africa. In 2007 the HIV prevalence among pregnant women attending antenatal clinics was >20% in the southern African counties of Botswana, Swaziland, South Africa and Lesotho. Mother-to-child transmission (MTCT) of HIV can occur in-utero, intrapartum or postnatally. Without any preventive measure the overall rate of the MTCT of HIV in breastfeeding women could be 25-45%. Prior to the discovery of successful antiretroviral interventions to prevent the MTCT of HIV in sub-Saharan Africa (before 1999), innovative research determined the magnitude of the problem, the impact of the HIV epidemic on mothers and children, and the main risk factors associated with MTCT. Non-antiretroviral interventions conducted before 1999 such as washing the birth canal with antiseptics and antenatal supplementation with vitamin A did not reduce the MTCT of HIV. However, during the period 1999 to present, major successes were made in the prevention of the MTCT of HIV. The use of single-dose nevirapine prophylaxis to the mother and infant reduced the MTCT of HIV to ~12%. Subsequently, longer prophylaxis and combined antiretroviral regimens were shown to be highly effective and very low HIV transmission rates comparable to those in developed countries were reported in some clinical trial settings in sub-Saharan Africa. The future is promising but challenges remain. The current successful intervention modalities are entirely dependent on antiretrovirals and breastfeeding continues to be vital for the survival of the child in the African setting. Reviewing past and present achievements assists in focusing future research and development of prevention programs.     

Impact of Maternal HIV Seroconversion during Pregnancy on Early Mother to Child Transmission of HIV (MTCT) Measured at 4-8 Weeks Postpartum in South Africa 2011-2012: A National Population-Based Evaluation

Background

Mother-to-child transmission of HIV (MTCT) depends on the timing of HIV infection. We estimated HIV-seroconversion during pregnancy (HSP) after having a HIV-negative result antenatally, and its contribution to early MTCT in South Africa (SA).

Methods and Findings

Between August 2011 and March 2012, we recruited a nationally representative sample of mother-infant pairs with infants aged 4-to-8 weeks from 578 health facilities. Data collection included mother interviews, child health-card reviews, and infant dried-blood-spots sample (iDBS). iDBS were tested for HIV antibodies and HIV-deoxyribonucleic-acid (HIV-DNA). HSP was defined as maternal self-report of an HIV-negative test during this pregnancy, no documented use of antiretroviral drugs and a matched HIV sero-positive iDBS. We used 20 imputations from a uniform distribution for time from reported antenatal HIV-negative result to delivery to estimate time of HSP. Early MTCT was defined based on detection of HIV-DNA in iDBS. Estimates were adjusted for clustering, nonresponse, and weighted by SA’s 2011 live-births.

Results

Of 9802 mother-infant pairs, 2738 iDBS were HIV sero-positive, including 212 HSP, resulting in a nationally weighted estimate of 3.3% HSP (95% Confidence Interval: 2.8%-3.8%). Median time of HIV-seroconversion was 32.8weeks gestation;28.3% (19.7%- 36.9%) estimated to be >36 weeks. Early MTCT was 10.7% for HSP (6.2%-16.8%) vs. 2.2% (1.7%-2.8%) for mothers with known HIV-positive status. Although they represent 2.2% of all mothers and 6.7% of HIV-infected mothers, HSP accounted for 26% of early MTCT. Multivariable analysis indicated the highest risk for HSP was among women who knew the baby’s father was HIV-infected (adjusted-hazard ratio (aHR) 4.71; 1.49-14.99), or who had been screened for tuberculosis (aHR 1.82; 1.43-2.32).

Conclusions

HSP risk is high and contributes significantly to early MTCT. Identification of HSP by repeat-testing at 32 weeks gestation, during labor, 6 weeks postpartum, in tuberculosis-exposed women, and in discordant couples might reduce MTCT.     

Greater adherence to highly active antiretroviral therapy (HAART) between pregnant versus non-pregnant women living with HIV.

One of the most remarkable advances in the control of the HIV/AIDS pandemic has been the introduction of highly active antiretroviral therapy (HAART). The use of HAART has been associated to reductions in AIDS-related mortality in most countries where HAART is available. Unfortunately, the adherence required to keep good control of viral replication is higher than what is required in other medical conditions. Several studies have shown a relationship between adherence and viral suppression ranging between 90-95% required for complete suppression. Multiple factors have been related to adherence among which are: gender, racial/ethnic distribution, age, personality traits, education, alcohol use and others. For women living with HIV there might be additional difficulties to handle in order to be adherent (i.e. multiple family responsibilities). A group of 165 women living with HIV attending a multidisciplinary clinic were interviewed with a 3-day adherence questionnaire. Correlation with clinical information was obtained from the Clinic Data Base. A total of 37 pregnant and 128 non-pregnant women were included in this analysis, 96% of which were on HAART. Complete adherence (100%) was reported by 91% of the pregnant and 70% of the non-pregnant women. (Fisher's exact test 0.009). The majority, 99% knew the names of their medications. There were no differences among groups in scholarity, history or actual cigarette smoking, history or actual drug use, CD4 lymphocyte counts (median or proportion below 350 cells/mm3), mean HIV RNA viral load or the proportion of patients with HIV RNA < 1,000 copies/ml. The transmission rate for the sample of pregnant women was zero. The reported adherence rates to HAART for women living with HIV were highest among the pregnant women. This difference was statistically significant (Chi Sq 0.05). The great majority (93%) reported knowing the names of the medications. In spite of reported barriers to adherence, pregnant women attending a multidisciplinary clinic for HIV care and research, reported good rates of adherence to HAART. This is also reflected in the good perinatal outcomes. Non-pregnant women with lower adherence rates might need additional interventions to improve adherence.     

Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection

Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11 alpha, alpha(E)beta 7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.     

Substance use and HIV disease progression in the HAART era: implications for the primary prevention of HIV

Prior to the era of highly active anti-retroviral therapy (HAART), cohort studies provided equivocal evidence to support the hypothesis that substance use predicts more rapid HIV disease progression. The present review examined the effects of substance use on HIV disease progression in cohort studies with follow-up that continued into the HAART era. Of the 20 studies included in this review, 16 observed that substance use predicted at least one indicator of HIV disease progression. Ten of the 11 studies that followed participants exclusively in the HAART era observed an effect of substance use on HIV disease progression. Findings across studies indicate that stimulant use promotes more rapid HIV disease progression and the effects of substance use on HIV disease progression can persist after controlling for self-reported HAART non-adherence. Future investigations that examine the bio-behavioral pathways whereby substance use promotes HIV disease progression should include: measures of HIV genotypic and phenotypic resistance, multi-method assessment of adherence, and assessment of co-morbid infections that are more prevalent among substance users. Although further mechanistic research is needed, findings from existing cohort studies have clear clinical implications. Implementing screening, brief intervention and referral to substance abuse treatment in HIV medical care could optimize health outcomes and decrease HIV transmission rates by boosting the effectiveness of "Test and Treat" approaches to HIV prevention.     

Analysis of HIV Early Infant Diagnosis Data to Estimate Rates of Perinatal HIV Transmission in Zambia

Background

Mother-to-child transmission of HIV (MTCT) remains the most prevalent source of pediatric HIV infection. Most PMTCT (prevention of mother-to-child transmission of HIV) programs have concentrated monitoring and evaluation efforts on process rather than on outcome indicators. In this paper, we review service data from 28,320 children born to HIV-positive mothers to estimate MTCT rates.

Method

This study analyzed DNA PCR results and PMTCT data from perinatally exposed children zero to 12 months of age from five Zambian provinces between September 2007 and July 2010.

Results

The majority of children (58.6%) had a PCR test conducted between age six weeks and six months. Exclusive breastfeeding (56.8%) was the most frequent feeding method. An estimated 45.9% of mothers were below 30 years old and 93.3% had disclosed their HIV status. In terms of ARV regimen for PMTCT, 32.7% received AZT+single dose NVP (sdNVP), 30.9% received highly active antiretroviral treatment (HAART), 19.6% received sdNVP only and 12.9% received no ARVs. Transmission rates at six weeks when ARVs were received by both mother and baby, mother only, baby only, and none were 5.8%, 10.5%, 15.8% and 21.8% respectively. Transmission rates at six weeks where mother received HAART, AZT+sd NVP, sdNVP, and no intervention were 4.2%, 6.8%, 8.7% and 20.1% respectively. Based on adjusted analysis including ARV exposures and non ARV-related parameters, lower rates of positive PCR results were associated with 1) both mother and infant receiving prophylaxis, 2) children never breastfed and 3) mother being 30 years old or greater.Overall between September 2007 and July 2010, 12.2% of PCR results were HIV positive. Between September 2007 and January 2009, then between February 2009 and July 2010, proportions of positive PCR results were 15.1% and 11% respectively, a significant difference.

Conclusion

The use of ARV drugs reduces vertical transmission of HIV in a program setting. Non-chemoprophylactic factors also play a significant role in HIV transmission. The overall change in the proportions of positive PCR results over time is more likely an indication of better PMTCT implementation. Determination of the outcomes of PMTCT in program settings is feasible but requires accurate documentation and analysis.     

The relative risks and etiologic fractions of different causes of death and disease attributable to alcohol,tobacco and illicit drug use in Canada

BACKGROUND: In 1996 the number of deaths and admissions to hospital in Canada that could be attributed to the use of alcohol, tobacco and illicit drugs were estimated from 1992 data. In this paper we update these estimates to the year 1995. METHODS: On the basis of pooled estimates of relative risk, etiologic fractions were calculated by age, sex and province for 90 causes of disease or death attributable to alcohol, tobacco or illicit drugs; the etiologic fractions were then applied to national mortality and morbidity data for 1995 to estimate the number of deaths and admissions to hospital attributable to substance abuse. RESULTS: In 1995, 6507 deaths and 82,014 admissions to hospital were attributed to alcohol, 34,728 deaths and 194,072 admissions to hospital were attributed to tobacco, and 805 deaths and 6940 admissions to hospital were due to illicit drugs. INTERPRETATION: The use and misuse of alcohol, tobacco and illicit drugs accounted for 20.0% of deaths, 22.2% of years of potential life lost and 9.4% of admissions to hospital in Canada in 1995.     

The Cost-Effectiveness of Directly Observed Highly-Active Antiretroviral Therapy in the Third Trimester in HIV-Infected Pregnant Women

Background

In HIV-infected pregnant women, viral suppression prevents mother-to-child HIV transmission. Directly observed highly-active antiretroviral therapy (HAART) enhances virological suppression, and could prevent transmission. Our objective was to project the effectiveness and cost-effectiveness of directly observed administration of antiretroviral drugs in pregnancy.

Methods and Findings

A mathematical model was created to simulate cohorts of one million asymptomatic HIV-infected pregnant women on HAART, with women randomly assigned self-administered or directly observed antiretroviral therapy (DOT), or no HAART, in a series of Monte Carlo simulations. Our primary outcome was the quality-adjusted life expectancy in years (QALY) of infants born to HIV-infected women, with the rates of Caesarean section and HIV-transmission after DOT use as intermediate outcomes. Both self-administered HAART and DOT were associated with decreased costs and increased life-expectancy relative to no HAART. The use of DOT was associated with a relative risk of HIV transmission of 0.39 relative to conventional HAART; was highly cost-effective in the cohort as a whole (cost-utility ratio $14,233 per QALY); and was cost-saving in women whose viral loads on self-administered HAART would have exceeded 1000 copies/ml. Results were stable in wide-ranging sensitivity analyses, with directly observed therapy cost-saving or highly cost-effective in almost all cases.

Conclusions

Based on the best available data, programs that optimize adherence to HAART through direct observation in pregnancy have the potential to diminish mother-to-child HIV transmission in a highly cost-effective manner. Targeted use of DOT in pregnant women with high viral loads, who could otherwise receive self-administered HAART would be a cost-saving intervention. These projections should be tested with randomized clinical trials.     

The gut mucosal viral reservoir in HIV-infected patients is not the major source of rebound plasma viremia following interruption of highly active antiretroviral therapy

Interruption of suppressive highly active antiretroviral therapy (HAART) in HIV-infected patients leads to increased HIV replication and viral rebound in peripheral blood. Effects of therapy interruption on gut-associated lymphoid tissue (GALT) have not been well investigated. We evaluated longitudinal changes in viral replication and emergence of viral variants in the context of T cell homeostasis and gene expression in GALT of three HIV-positive patients who initiated HAART during primary HIV infection but opted to interrupt therapy thereafter. Longitudinal viral sequence analysis revealed that a stable proviral reservoir was established in GALT during primary HIV infection that persisted through early HAART and post-therapy interruption. Proviral variants in GALT and peripheral blood mononuclear cells (PBMCs) displayed low levels of genomic diversity at all times. A rapid increase in viral loads with a modest decline of CD4(+) T cells in peripheral blood was observed, while gut mucosal CD4(+) T cell loss was severe following HAART interruption. This was accompanied by increased mucosal gene expression regulating interferon (IFN)-mediated antiviral responses and immune activation, a profile similar to those found in HAART-naive HIV-infected patients. Sequence analysis of rebound virus suggested that GALT was not the major contributor to the postinterruption plasma viremia nor were GALT HIV reservoirs rapidly replaced by HIV rebound variants. Our data suggest an early establishment and persistence of viral reservoirs in GALT with minimal diversity. Early detection of and therapy for HIV infection may be beneficial in controlling viral evolution and limiting establishment of diverse viral reservoirs in the mucosal compartment.     

CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals

The basis for the extensive variability seen in the reconstitution of CD4(+) T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4(+) T cells/mm(3). The CCL3L1-CCR5 genotypes favoring CD4(+) T cell recovery are similar to those that blunted CD4(+) T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, CCL3L1-CCR5 variations influence HIV pathogenesis even in the presence of HAART and, therefore, may prospectively identify subjects in whom earlier initiation of therapy is more likely to mitigate immunologic failure despite viral suppression by HAART. Furthermore, as reconstitution of CD4(+) cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution.     

The role of HIV replicative fitness in perinatal transmission of HIV

Perinatal transmission of Human immunodeficiency virus(HIV),also called mother-to-child transmission(MTCT),accounts for 90% of infections in infants worldwide and occurs in 30%-45% of children born to untreated HIV-1 infected mothers.Among HIV-1 infected mothers,some viruses are transmitted from mothers to their infants while others are not.The relationship between virologic properties and the pathogenesis caused by HIV-1 remains unclear.Previous studies have demonstrated that one obvious source of selective pressure in the perinatal transmission of HIV-1 is maternal neutralizing antibodies.Recent studies have shown that viruses which are successfully transmitted to the child have growth advantages over those not transmitted,when those two viruses are grown together.Furthermore,the higher fitness is determined by the gp120 protein of the virus envelope.This suggests that the selective transmission of viruses with higher fitness occurred exclusively,regardless of transmission routes.There are many factors contributing to the selective transmission and HIV replicative fitness is an important one that should not be neglected.This review summarizes current knowledge of the role of HIV replicative fitness in HIV MTCT transmission and the determinants of viral fitness upon MTCT.