Antenatal Care - Treatment

A systematic review of the literature on the relationship between pregnancy and HIV disease progression in the context of HAART with six research studies found that “...the general consensus remains that the potential side effects of HAART use for HIV-positive women during pregnancy appear to be minimal, but further research is required” . However, studies suggest that pregnant HIV-positive women on HAART have the lowest risk of HIV disease progression, compared with pregnant HIV- positive women on other forms of treatment (MacCarthy et al., 2009).

A 2007 Cochrane review on antiretrovirals used to prevent perinatal transmission of HIV found that antiretroviral treatment during the perinatal period (antenatal and peripartum) significantly reduced the risk of HIV transmission in comparison with placebo. For zidovudine, the length of treatment was significantly associated with risk of HIV transmission. Longer treatments during the antenatal period appear to significantly lower infant risk of HIV acquisition. Moreover, for mothers, a short-course of zidovudine and lamivudine during pregnancy, labor, and postpartum along with a single dose of nevirapine during labor is especially effective in reducing perinatal transmission. For infants of HIV-positive mothers who have not received antiretroviral prophylaxis, treatment with a single dose of nevirapine along with one week of zidovudine reduced the risk of HIV acquisition. No significant adverse events were identified for either mothers or their infants after antiretroviral use to prevent perinatal transmission.

A study from the USA that analyzed data from 2,543 HIV-positive women attending clinics at various sites correlating HAART use during pregnancy with maternal and pregnancy outcomes found that the benefits of antiretroviral treatment outweighed the risks. Maternal outcomes assessed included hematologic, gastrointestinal, neurologic, renal and dermatologic complications; gestational diabetes; lactic acidosis; and death. Logistic regression analyses controlling for multiple covariates revealed HAART to be independently associated with few maternal complications.

Secondary data analysis from a completed randomized trial assessing nevirapine versus zidovudine in reducing PMTCT in Uganda found that maternal viral load was the best predictor of both early and late perinatal transmission. Treatment with HAART lowers maternal viral load. Of 610 infants who were evaluated for HIV acquisition, 99 were infected in the early transmission period (first positive HIV RNA PCR obtained before 56 days of age) and 23 were infected in the late transmission period (after 56 days of age). In the multivariate model, six to eight weeks postpartum maternal log10viral load, with a hazard ratio of 3.66, was the strongest predictor of HIV transmission. Pre-entry maternal log10 viral load was also significantly associated with early transmission, hazard ratio of 2.11.

A study from Nigeria successfully demonstrated the transition from nevirapine for PMTCT to HAART for both PPT and improved maternal health. With HAART, rates following HAART (3.6%) were lower than PPT rates using ZDV plus nevirapine (5.2%) or nevirapine only (7.1%) in 1,138 HIV-exposed babies. Almost half of the women delivered at home or in peripheral health facilities.

A 2004-2007 study in South Africa followed 302 women, who initiated HAART at an antenatal ARV clinic, and found a perinatal transmission rate of 5%. Women who received more than seven weeks of HAART during pregnancy had a perinatal transmission rate of 0.3%. The study analyzed 689 women who had not previously received treatment for HIV and began treatment with HAART while pregnant. These women were followed weekly for eight weeks until stable. HIV status was determined by HIV-1 DNA testing. The study also routinely screened for syphilis. Women were excluded if they conceived while initiating HAART. About 300 women were diagnosed with HIV during the current pregnancy. The study also found that 23% of women were aware of their HIV status before conception and did not seek medical care until the third trimester. Of 455 women providing data on delivery, 56.9% delivered vaginally, 25.7% underwent cesarean sections for reasons not related to HIV and 17.4% had emergency cesarean sections. Of 244 women who provided follow-up data, 80% experienced an increase in CD4 cell count and of 211 women who provided data on viral load, 80.5% experienced a decrease in viral load over 15 weeks. All infants born HIV-positive were born to women who received seven or fewer weeks of HAART. “Recent data suggest that pregnancy is associated with a lower risk of HIV disease progression, and experience with the ANC ARV cohort supports this finding” . This study was constrained by a national policy restricting viral load testing to twice a year. Among women who did have viral load testing, 75.6% had an undetectable viral load (Black et al., 2008).

A study assessing perinatal transmission in Botswana from 2006 to 2007 found an HIV transmission rate of approximately 3.6% for women receiving antiretrovirals either for prophylaxis for PMTCT only or as indicated for the mother’s health. Pregnant women with CD4 counts above 200/µl received zidovudine starting at 28 weeks of gestation until labor along with a single dose of nevirapine at the onset of labor. Women with CD4 counts below 200/µl initiated HAART before or during pregnancy. Uptake of either short-term treatment or HAART was 90%. Dried blood spot HIV testing was completed for 10,516 children born to HIV-positive mothers during the study period. Mothers who initiated HAART before pregnancy were the least likely to transmit HIV to their infant as opposed to women who initiated HAART during pregnancy, women who received a short course of zidovudine and a single dose of nevirapine, women who received only zidovudine, women who received only single dose nevirapine, and women who received no treatment. The added benefits of a single dose of nevirapine for mothers who had received zidovudine for more than four weeks was found to be negligible, although for mothers receiving no treatment a single dose nevirapine reduced MTCT by 40%.

A study from 1999 to 2005 of 551 infants born to HIV-positive women seen at GHESKIO, Haiti, found that prior to HAART availability in 2003, infant mortality was 23 per 100 live births per year. Following the introduction of HAART for HIV-positive women, infant mortality fell to 7 per 100 live births in 2005. In the cohort of 399 women given exclusively single drug prophylaxis, the perinatal transmission rate was 10%. In the 60 women who received HAART the perinatal transmission rate was 1.9%..

A prospective cohort study from 2002 to 2006 enrolling HIV-positive pregnant women in Latin America and Caribbean countries found that MTCT rates were very low, most women had viral loads below 1000 copies/mL, almost all women were receiving antiretroviral treatment either for prophylaxis or for the mother’s health, and many women chose elective cesarean section to further reduce the risk of MTCT. Of 770 mother-infant pairs included, 87 percent of women had viral loads below 1000 copies/mL, 99 percent of women received one or more antiretrovirals during pregnancy, and 41 percent delivered through elective cesarean section. Less than one percent of infants were diagnosed as HIV-positive at the end of the study period.

A study from the United States from 1997 to 2004 with 759 HIV-positive women (139 pregnant women and 620 non-pregnant women) receiving HIV care found that in comparison to non-pregnant women, pregnant women had a lower risk of HIV disease progression (defined as an AIDS defining event or death). All pregnant women were treated with either HAART (86%) or non-HAART ART (14%). In comparison, 68% of non-pregnant women were treated with HAART, 9% with non- HAART ART and 23% received no treatment. At the end of the study period 5% of pregnant vs. 7% of non-pregnant women experienced an AIDS-defining event only, 1% of pregnant vs. 11% of non-pregnant women died and 2% of pregnant vs. 7% of non-pregnant women experienced both an AIDS-defining event and death. Overall 8% of pregnant women vs. 24% of non-pregnant women experienced an AIDS- defining event or death. Other predictors of disease progression included a baseline CD4 count of greater than 200 cells/mm3, a baseline HIV-1 RNA level of greater than 10,000 copies/mL, maternal age, HAART duration, non-HAART ART duration and durable virologic suppression. The effect of pregnancy on slower disease progression was still significant after controlling for these previously listed clinical variables. Finally, women with more than one pregnancy tended to have a lower risk of disease progression than women with only one pregnancy; however, this association was not statistically significant.

A study from Côte d’Ivoire that enrolled HIV-positive pregnant women between 2003 and 2005 in an MTCT-Plus program found that antiretroviral treatment for pregnant women, both indicated for the mother’s health as well as solely for PMTCT purposes, was effective and safe. Women with CD4 counts below 200 cells/mm3 were considered eligible for HAART for their own health and received a treatment combination of mainly zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP). Women not eligible for HAART for their own health received a short course of ARVs, mainly ZDV and 3TC from 32 weeks of pregnancy until 3 days postpartum and a single dose of NVP during labor; ZDV from 28 weeks of pregnancy; single dose NVP; or ZDV and single dose NVP. All infants in the sample received ZDV syrup for 7 days after birth and a single dose of NVP 3 days after birth regardless of mother’s ARV regimen. Of the 261 HIV- infected women identified and enrolled in the study, 57% (143) received short- course ARVs and 43% (107) received HAART. Overall, the HIV status of 97.4% (225) children was determined with 12 confirmed HIV infections. The probability of peripartum HIV infection was 2.2% for children born to mothers using HAART and 3.1% for children born to mothers using short-course ARVs. The only factor found to be significant in peripartum HIV acquisition was low birth weight, while infant feeding practice, gender, maternal ARV regimen, CD4 count and age were not significant..

A 2002 study in Nigeria found that among the 32 women who were given HAART, transmission of HIV to infants was 9.1%. Among the 22 women who had single dose nevirapine in labor there was a transmission rate of over 33%. The best outcome was among those that had HAART, an elective C-section and did not breastfeed; none of the babies were HIV-positive at 18 months. “It is recommended that the single dose nevirapine be abandoned in favour of combination treatment… The single dose nevirapine ….may lead to the spread of a nevirapine-resistant strain”.

A study in Mozambique from 2002 to 2005 of 985 HIV-positive pregnant women found that HAART was more widely accepted than single-dose nevirapine in earlier studies, with 80% completing a treatment protocol of HAART until six months postpartum and beyond. Maternal mortality was 0.8%, with vertical transmission rates of 1.4% at six months, equivalent to those developed countries.

A study in Jamaica with over 69,995 pregnant women presenting for antenatal care between 2005 and 2007 found that the use of HAART decreased perinatal transmission from 6% to 1.6% in 3 urban areas and to 4.75% island- wide.

A 2009 study from Thailand found that one month of zidovudine (ZDV 300 mg twice daily) and didanosine (ddI400 mg once daily) following a single dose of nevirapine (NVP) during labor prevented almost all NNRTI resistance. Two hundred and twenty ARV-näive HIV-positive pregnant women with CD4 counts greater than 250 cells/mm3 receiving postpartum ZDV treatment during the third trimester, single dose NVP during labor, and 1 month of ZDV/ddI were matched with women (with similar CD4 counts) receiving ZDV treatment during the third trimester and single dose NVP during labor (but no postpartum treatment). Resistance mutations were found in 1.8% of women who received the 1 month postpartum ZDV/ddI and in 20.7% of the women who did not receive postpartum treatment.

A study from Thailand that enrolled 169 HIV-positive pregnant women (28 to 38 weeks gestation) from 2006 to 2008 found that postpartum antiretroviral treatment for at least 7 days after a single dose of intrapartum nevirapine (NVP) significantly reduced the development of NVP resistance. Women included in the study had CD4 counts of greater than 250 cells/mm3, may or may not have received zidovudine (ZDV) during their current pregnancy or a past pregnancy, and were not intending to receive ART within 8 weeks postpartum. Overall, 169 women received either ZDV, didanosine (ddI), and lopinavir/ritonavir (LPR/r) for 7 days postpartum; ZDV and ddI for 30 days postpartum; or ZDV, ddI, and LPV/r for 30 days postpartum (after receiving intrapartum single dose NVP). These 3 treatment groups were compared to a historic control group from a 2001 to 2003 study of 119 women who had received prenatal ZDV treatment and intrapartum single dose NVP, but no postpartum treatment regimen. In comparison to the control group, women receiving any of the three postpartum treatments had a significantly lower risk of developing NVP resistance.

A study enrolling HIV-positive pregnant women not requiring HAART for their own health in Côte D’Ivoire, Cambodia and South Africa from 2006 to 2007 found that a combination of tenofovir disoproxil fumarate and emtricitabine taken along with single-dose nevirapine at delivery and for 7 days postpartum was effective in preventing nevirapine resistance and was well tolerated. All study participants also received antenatal zidovudine. Of 38 women included in the study no resistance mutations for any antiretroviral were detected one month after delivery and no cases of MTCT were found. Nine serious adverse events were documented in women and eleven in infants, including four infant deaths, although these were determined unlikely to be related to antiretroviral exposure.

A study in South Africa between 2005 and 2007 showed that prevention of perinatal transmission of HIV through combined use of ZDV from 34 weeks of pregnancy and a single dose of NVP during delivery reduced NVP resistance rates reported by previous studies. Seventy-six pregnant women not yet qualified for antiretroviral treatment (CD4 count above 200/µl and no AIDS defining illness) were included in this study, with 13 (17.1%) presenting NVP resistance mutations approximately 6 weeks after delivery.

A review of seven randomized MTCT intervention trials looked at the effect of maternal health, infant HIV infection, feeding practices and age at acquisition of infection on the rate of child mortality among 3,468 African children born to HIV-positive women. Child mortality was associated with maternal death, CD4 cell counts <200 and infant infection and varied by region (east, west and southern Africa), with overall rate of more than 50% of vertically infected children dying by age 2.

A retrospective cohort study with more than ten years of follow-up in Malawi found that mortality in children less than five years was much higher in children born to HIV-positive mothers than in those born to HIV-negative mothers. Among those with HIV-positive mothers, mortality was 27% as infants, 46% for those under five years, and 49% for those under ten years of age. For those with HIV-negative mothers, mortality was 11% as infants, 16% under the age of five, and 17% under the age of ten.

Children left motherless are 3 to 10 times more likely to die within two years than children who live with both parents.

A retrospective review of clinical records of 571 HIV-positive pregnant women in antenatal care in Jamaica between 2002 and 2006 found that national scale up of HAART improved maternal and infant outcomes. Acceptance of HAART increased: from 2002-2004, HAART was used by 2 to 3% of pregnant women; by 2006, 62% of HIV-positive women accessed HAART during pregnancy. From 2002 to 2005, zidovudine and/or nevirapine were used. For all four years, 24 maternal deaths occurred. Of these, 23 or 96% occurred in those who took zidovudine/nevirapine, with only one death or 4% occurring in those who accessed HAART. By bringing viral load to an undetectable level, HAART has minimized the “chance of perinatal transmission to under 2% in Kingston and under 5% islandwide” . Between 2002 and 2005, only 1% received HAART despite 8% of patients having been clinically assessed as warranting HAART. In 2008, “we offer four-drug HAART…. to all HIV-infected women who are diagnosed early in pregnancy, with island-wide uptake consistently approaching 90% regardless of the woman’s individual disease stage” (Johnson et al., 2008: 221). Recent island-wide upgrade of lab facilities allowing wide availability of CD4 counts and viral loads has “already minimized peripartum deaths in pregnant women with HIV infection” (Johnson et al., 2008:220).

A review of PMTCT programs in Ukraine found substantial improvements in MTCT on a national level. MTCT rates decreased from 15.2% in 2001 to 7% in 2006. By January 2008, 3,356 mother-child pairs had received PMTCT services. Among women receiving no ARV prophylaxis, the PPT rate was 26.7%, decreasing to 15.7% for women who received single dose nevirapine, 7% for women receiving zidovudine; 9.2% for women who received both zidovudine and single dose nevirapine and 3.9% among women who accessed HAART. Maternal HIV clinical disease stage (WHO clinical stages 1 and 2) as compared to WHO clinical stages 3 and 4 were not significantly associated with PMTCT. PMTCT rates more than halved between 2001 and 2006, with a PMTCT rate of one in 14 in 2006. Use of HAART is planned for all HIV-positive women in Ukraine’s next PMTCT program. Most women received their first HIV diagnosis in pregnancy.

An evaluation in Zambia that compared integration of antiretroviral therapy in antenatal care to referral to ART care found that where antiretroviral therapy was integrated with antenatal care, women were more than twice as likely to be enrolled while pregnant and within 60 days of HIV diagnosis and to have initiated ART while pregnant. Between 2007 and 2008, 13,917 women started antenatal care more than 60 days before the intervention rollout and constituted the control cohort; 17,619 women started antenatal care after ART was integrated into ANC and constituted the intervention cohort. Of the 1,566 patients found eligible for ART, 376 out of 846 (44.4%) enrolled while pregnant and within 60 days of HIV diagnosis as compared with 181 of 716 (25.3%) who were referred for ART. 278 out of 846 (32.9%) of women who accessed ART in integrated services in ANC initiated ART while pregnant compared to 103 of 716 (14.4%) of those who were referred for ART. Women found to be HIV-positive through antenatal testing had a specimen routinely sent for a CD4 cell count. Separate ART facilities were located on the same premises but physically separate and separately staffed.

A study of 872 women in Zambia found that HAART was less effective among women who had been exposed to single dose nevirapine. HIV-positive women who had received single dose nevirapine between 2001 and 2005 who could be contacted were evaluated for eligibility for HAART if they had CD4 counts under 200 or viral counts under 35 and evidence of WHO clinical disease stage 3” . . Mortality in women who met ART eligibility criteria was high with 23.7% mortality by 24 months in the era before ART became available. Of 161 single dose nevirapine exposed women who were still on HAART after six months, 70.8% achieved a viral load less than 400 copies per milliliter and 40.4% achieved a viral load less than 50 copies per milliliter. Of eight women exposed to single dose nevirapine within six months of starting HAART, only three achieved a viral load of less than 400 copies per milliliter by six months after therapy compared with 59.1% of 22 women who started HAART within six to 12 months after single dose nevirapine and, 72.1% of 61 who started HAART within 12 to 24 months, and 77.1% of 70 who started more than 24 months after exposure. “With HIV treatment programs now in place, women should be screened for ART during pregnancy” (Kuhn et al., 2009b: 135). “If ART is available, pregnant women should be prioritized and started on therapy if eligible as a matter of urgency… These results emphasize the importance of establishing appropriate referrals and coordination between services so that pregnant HIV-infected women can be triaged for ART if appropriate” (Kuhn et al., 2009b: 136).

Training a key obstetrician on antiretroviral treatment at a medical center in Tanzania resulted in 25 women needing HAART gaining timely access to treatment.

In a study at Coronation Women and Children Hospital, South Africa, data were gathered from HIV-positive women attending antenatal care from June 2004 to July 2005 to evaluate linking antenatal with antiretroviral treatment (ARV) services. After a patient record review, interventions were implemented to strengthen service linkages and integrate ARV treatment within antenatal care. Laboratory investigations were streamlined, including CD4 cell count testing at the first antenatal visit. MTCT risk for women initiating ARV treatment was compared with that of women-infant pairs receiving single-dose nevirapine (sd- NVP). In total, 164 pregnant women initiated ARV treatment and 863 received sd-NVP. After changes to service delivery, time-to-treatment initiation was reduced from a median of 56 days to 37 days. The risk of MTCT for women receiving ARV treatment was lower than for those given sd-NVP.

A study from Côte d’Ivoire evaluating an MTCT-plus program from 2003 to 2005 found a significant increase in antiretroviral treatment initiation and high rates of retention in care for women and their partners. Of the 605 women enrolled during the study period, fewer than 2% of women and 9% of their partners were receiving antiretroviral treatment prior to enrollment in the program, in comparison to 41.5% of women and 65% of their partners after enrollment at the close of the study period. Retention rates were also high: only 2.5% of women and 5.5% of partners initiating ART were lost to follow-up, while 2% of women and 0% of partners not eligible for ART were lost to follow- up.

A study in rural Uganda providing PMTCT-Plus resulted in vertical HIV transmission rate dropping from over 27% to 8%; a HAART adherence rate of more than 95% for 80% of clients and an overall 36-month mortality rate of 8%. The program reached 16,000 pregnant women, 1,454 children and 683 men with VCT and HIV services. Services consisted of patient monitoring using WHO clinical staging, generic antiretroviral drugs and rapid HIV testing. Social services included nutrition interventions, loans and home based water chlorination. All services were incorporated into reproductive health services . (Abstract)