Black V, Hoffman RM, Sugar CA, Menon P, Venter F, Currier JS, Rees H. Safety and efficacy of initiating highly active antiretroviral therapy in an integrated antenatal and HIV clinic in Johannesburg, South Africa. J Acquir Immune Defic Syndr 2008 Nov 1; 49(3):276-281.
To describe the safety and efficacy of highly active antiretroviral therapy (HAART) in pregnant women treated in an integrated antenatal antiretroviral clinic (ANC ARV).
A retrospective analysis was performed on data from the ANC ARV cohort from August 2004 through February 2007. Data were collected by the ANC ARV care team, which consists of a physician, nurse, and counselor. Women who conceived on HAART were excluded for this analysis.
Johannesburg Hospital, South Africa
Data were collected on all treatment-naive women referred to the clinic who were subsequently initiated on HAART during pregnancy (n=689). The mean age of the cohort was 29.2 years (SD: 5.0, range 18-48 years). The timing of HIV diagnosis was obtained in 388 women of whom 77.3% were diagnosed during the current pregnancy. Of 410 women with prior pregnancy data available, 11.5% (n=47) were primiparous. The mean number of pregnancies per woman was 2.7 (SD: 1.1 and range 1-8). Only 1.6% (n=11) of multiparous women reported taking single dose nevirapine (sdNVP) for prevention of mother-to-child transmission (PMTCT) during a prior pregnancy. The mean baseline CD4+ cell count performed at first clinic visit for the majority of women was 154 cells per microliter (n=639, SD: 92, range 6-784 cells/µ L), with 81.3% of women having CD4 counts below 200 cells per microliter. The mean baseline HIV-1 viral load was 101,561 copies per milliliter and SD was 177,585 copies per milliliter. The distribution of viral loads was asymmetric, with a skew toward lower ranges, as demonstrated by the median baseline HIV-1 viral load (n=452) of 29,000 copies per milliliter. The most common opportunistic infection (OI) at presentation was tuberculosis (7.7%). Serious OIs identifed at baseline included cryptococcal meningitis (0.4%) and Kaposi sarcoma (0.3%). The mean gestational age at HAART initiation was 27 weeks (data available on 437 women), and the mean number of weeks on HAART during pregnancy was 10.4 (data available on 250 women). The most commonly utilized HAART regimen in the cohort was stavudine, lamivudine, and nevirapine (82% of 620 women for whom data were available).
An integrated ANC ARV clinic was established within an existing antenatal service at Johannesburg Hospital. The goals of the integrated ANC ARV are to expedite initiation of HAART in pregnant women qualifying for this service, both to improve maternal health and to prevent mother-to-child HIV transmission. Pregnant women are offered voluntary counseling and testing for HIV at their first antenatal visit. Those who tested HIV positive had a CD4 cell count specimen taken on the same day. Those with CD4+ counts less than 200 cells per microliter were referred to the ANC ARV clinic. As the program became established and the clinic's capacity expanded, a higher CD4 cell count cutoff (250 cells/µ L) was employed for referral into the clinic. HIV-infected women with WHO Stage 4 classification, poor obstetric history, and conditions requiring amniocentesis were also referred to the ANC ARV. Women who did not qualify for HAART were seen in routine antenatal clinics and received sdNVP for PMTCT as per national guidelines. All women with CD4+ counts below 200 cells per microliter were offered prophylactic co-trimoxazole, and all pregnant women received folate and iron supplementation. Upon entering care at the ANC ARV clinic, women had baseline clinical assessment, laboratory testing, and adherence counseling. At the follow-up visit 1 week later, a second adherence session was conducted, and if no mitigating factors existed, HAART was initiated. During the period of data collection, the first-line treatment regimen consisted of stavudine 30 or 40 mg tablets according to weight, lamivudine 150 mg tablets, and nevirapine 200 mg tablets. Nevirapine toxicity was monitored clinically and with alanine transaminase measurements. For cases of toxicity or resistance, alternative drugs included zidovudine, didanosine, ritonavir-boosted lopinavir (Kaletra® capsule), and efavirenz. Efavirenz was used in women with TB coinfection who were beyond the first trimester of pregnancy. Women were followed at the ANC ARV clinic weekly until stable on HAART. Stability was defined as a minimum of 8 weeks of treatment with absence of side effects and adequate adherence, defined as no missed doses for more than 2 consecutive visits (determined by pill count and self-report). Women who missed doses by self-report and/or pill count remained in the ANC ARV and received intensive follow-up adherence counseling. Those with no complications or ongoing opportunistic infections were then referred to community- based antenatal clinics for management to ensure that the ANC ARV clinic could continue to accommodate new patients. No routine postnatal follow-up existed when the ANC ARV was initiated. Pregnant women were referred to adult HAART clinics, with high rates of loss to follow-up during the referral process. In October 2005, a postnatal clinic (PNC) was established to follow postpartum women initiated on HAART during pregnancy and to provide postpartum HIV care for women identified with infection during the peripartum period. In addition, at 6 weeks postpartum, the PNC offers HIV testing for exposed infants (HIV-1 DNA Roche Amplicor). At 10 weeks postpartum, women are referred to a local HAART clinic for further care.
1. maternal adverse drug reactions; 2. maternal CD4+ cell counts; 3. maternal HIV-1 viral load; 4. mother-to-child HIV transmission as determined by HIV-1 DNA testing.
- Adverse drug reactions: The most common adverse reaction among women in the cohort was nevirapine-associated skin rash (18 episodes, 3.5%) including 2 women with Stevens-Johnson syndrome. Clinically signifcant nevirapine-associated hepatitis occurred in 1% of the cohort, with no deaths. Mitochondrial toxicities were rare with neuropathy reported in 2 women (0.3%), although the mean duration of exposure in the cohort was brief (10 weeks). Only 35 women received protease inhibitors at any point during pregnancy, and no adverse reactions were reported. Regimen changes during pregnancy were uncommon, with only 2.6% (n = 16, data available on 620 women) switching to a different regimen for serious toxicity.
- CD4+ cell counts: Follow-up CD4+ cell counts were done in most women who remained in the program for at least 24 weeks (n = 244). Of these women, 80% gained at least 50 or more cells per microliter a mean of 24 weeks after baseline, and half of this group (41.4%) gained 100-250 cells per microliter. Approximately 8.2% of women experienced a drop in CD4 cell count.
- HIV viral load: Baseline and follow-up HIV-1 viral load data were available in a subset of 211 women. At baseline, 44% of these women had viral loads greater than 50,000 copies per milliliter. A mean of 14.4 weeks later, 80.5% were suppressed to <1000 copies per milliliter and only 6 women continued to have viremia at a level of greater than 100,000 copies per milliliter.
- Mother-to-child HIV transmission and other infant outcomes: For 302 mother-infant pairs who completed 6 weeks of postnatal follow-up, the HIV-1 transmission rate was 5% (n=15). There were 11 women with fetal or infant loss, including 3 reports of intrauterine fetal demise, 3 stillbirths, and 5 neonatal deaths. One neonatal death was in an HIV-negative infant (cause unknown), the remaining 4 infant deaths had unknown HIV status. Two deaths were from unknown causes, and 2 were attributed to infection (gastroenteritis and pneumonia). The remainder of women did not return for infant HIV testing at 6 weeks postpartum (n=191, 27.7%) and therefore were classifed as lost to follow-up. Among those who completed follow-up infant HIV testing, the transmission rate for women who received more than 7 weeks of HAART during pregnancy was 0.3% (n=1). All but 2 neonates received sdNVP. Both these infants had follow-up HIV testing at 6 weeks, with 1 testing positive. The majority of women (99%) chose to formula feed.
The authors concluded that, within the ANC ARV program, initiating pregnant women on HAART was feasible, safe, and effective. Advanced gestational age at treatment initiation and loss to follow-up emerge as important challenges in this population.
There is no standardized measure of quality of studies of this design. However, the data analysis had a number of limitations. In this cohort, 27.7% of women did not return to the PNC for infant HIV testing. The issue of missing data and loss to follow-up of mother-infant pairs is signifcant. Missing data points are the result of referral to routine clinics after stabilization and return of women to rural homes around the time of delivery. Although ANOVA did not detect differences in mean age, baseline CD4 cell count, or baseline viral load for individuals who remained in the program as compared with those lost to follow-up, women who stayed in the ANC ARV program through the postnatal follow-up period may represent a distinctly different group based on socioeconomic factors, clinical status, and HIV infection characteristics. These differences are likely to bias the data, particularly in regard to HIV transmission rates.
The mother-to-child transmission rate for this group of women with advanced HIV disease was low (5%) compared with women who do not access HAART and is much lower than the rate of 11.1% reported from a recent study of healthier women (CD4 cell counts >200/µ L) who received sdNVP for PMTCT in Soweto, Johannesburg.(1) However, the number of infected infants in the ANC ARV cohort is high relative to developed countries where HAART is used for PMTCT and transmission rates are less than 2%.(2, 3) The high rate of HIV transmission relative to developed country settings is multifactorial, with these data reinforcing the importance of duration of HAART on rates of transmission. With 1 exception, all HIV-infected infants were born to women who received 7 or fewer weeks of HAART. Extensive use of stavudine in nonpregnant women in Africa has revealed high rates of mitochondrial toxicity, with overweight women particularly at risk for symptomatic and life-threatening lactic acidosis.(4) In this cohort of treatment-naive women initiating stavudine-containing regimens during pregnancy, adverse reactions were extremely rare. The low rates of observed toxicity may be due to the limited duration of nucleoside reverse transcriptase inhibitor exposure.
In South Africa, antenatal care, HIV treatment programs, and HIV prevention services are often delivered separately, and this division of health services creates barriers to comprehensive care. The ANC ARV program combines antenatal care, delivery of HAART to pregnant women with advanced HIV, and interventions for the prevention of mother-to-child HIV transmission in a coordinated and expedited fashion. Within the ANC ARV program, initiating women on HAART during pregnancy was feasible, safe, and effective. HAART-related complications were low, and in the subset of women on whom follow-up CD4+ cell counts and HIV viral loads were available, most had an excellent response to therapy with good short-term immune reconstitution and successful viral suppression. Advanced immunosuppression, late gestational age at presentation, and high rates of loss to follow-up emerge as important challenges in this population. As a result of the success of the ANC ARV at Johannesburg Hospital, 4 additional sites have been opened in the surrounding area, including 2 programs managed by midwives within primary health care clinics. It is anticipated that with ongoing support from public health leadership, sustainability will be attainable. This type of integrated program may be a crucial step toward closing the HIV treatment gap in South Africa.
- Martinson NA, Ekouevi DK, Dabis F, et al. Transmission rates in consecutive pregnancies exposed to single-dose nevirapine in Soweto, South Africa and Abidjan, Côte d'Ivoire. J Acquir Immune Defc Syndr. 2007;45:206-209.
- Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. 2002;29:484-494.
- Centers for Disease Control and Prevebntion. Achievements in public health. Reduction in perinatal transmission of HIV infection-United States, 1985-2005. MMWR Morb Mortal Wkly Rep. 2006;55:592-597.
- Geddes R, Knight S, Moosa MY, et al. A high incidence of nucleoside reverse transcriptase inhibitor (NRTI)-induced lactic acidosis in HIV-infected patients in a South African context. S Afr Med J. 2006; 96:722-724.