Short-course Antiretroviral Therapy Research Articles

The effect of short-course antiretroviral therapy initiated in primary HIV-1 infection on interleukin-6 and D-dimer levels.

Interruption of antiretroviral therapy (ART) in chronic HIV disease is associated with increased mortality, predicted by elevations in interleukin-6 (IL-6) and D-dimer. The effect of ART interruption in primary HIV-1 infection on these biomarkers is unknown. Plasma samples from 200 HIV seroconverters enrolled in the Short Pulse Anti-Retroviral Therapy At HIV Seroconversion trial of deferred ART (standard of care) - 12 or 48 week ART (ART12 or ART48, respectively) - were analysed for IL-6 and D-dimer at weeks 0, 12, 16, 48, 52, 60 and 108 after randomization. Changes in log10 levels from weeks 0 to 12 were analysed using linear regression, as were changes from baseline to 4 weeks after stopping ART. Areas under the biomarker-time curves (AUC) to week 108 were adjusted for baseline values, and compared across all arms. Median (inter-quartile range) baseline IL-6 and D-dimer were 1.45 (0.88, 2.41) pg/ml and 0.34 (0.20, 0.50) mg/l, respectively. At week 12, D-dimer levels were significantly lower among treated compared to untreated individuals (P < 0.001), whereas IL-6 levels were similar (P = 0.23). Within 4 weeks from stopping ART, IL-6 and D-dimer levels rose by 22 and 18%, reaching pre-ART levels. Over 108-week follow-up, there was no difference between arms in IL-6 AUC (P = 0.53), but D-dimer AUC was significantly lower for ART12 and ART48 compared to standard of care (overall P = 0.008). Stopping ART in primary HIV-1 infection leads to inflammatory biomarker rebound to pre-treatment levels. However, over 108-week follow-up, we found no evidence that biomarker levels were higher for those interrupting ART, compared to those remaining ART-naïve, and D-dimer levels were significantly lower.

Antiretroviral therapy in primary HIV infection

Evaluation of: SPARTAC Trial Investigators, Fidler S, Porter K et al. Short-course antiretroviral therapy in primary HIV infection. N. Engl. J. Med. 368, 207-217 (2013). The timing of antiretroviral therapy (ART) in patients who present with primary HIV infection is uncertain. This paper compared three strategies: ART for 48 weeks; ART for 12 weeks; or no therapy in 366 patients with primary HIV infection. They showed that 48 weeks of ART significantly reduced the risk of needing definitive therapy (after a median follow-up of 4.2 years). However, the median delay in needing to start definitive therapy (61 weeks) is not significantly greater than the amount of treatment given (48 weeks) to achieve this result, suggesting that the clinical benefit of immediate ART in primary HIV infection is not yet clear.

Influence of Short-Course Antenatal Antiretroviral Therapy on Viral Load and Mother-To-Child Transmission in Subsequent Pregnancies among HIV-Infected Women

HIV-infected women not requiring treatment for their own health usually receive short-course antiretroviral therapy (ART) during pregnancy. Little is known about the effect of this on response to HAART in subsequent pregnancies. We analysed data from the UK and Ireland's National Study of HIV in Pregnancy and Childhood for 2000-2010. Analyses were restricted to live births among women not on ART at conception but receiving antenatal HAART. We compared risk of detectable viral load at delivery and mother-to-child transmission in two pregnancy groups: 'ART-naive' and 'HAART-experienced' (≥7 days of HAART during previous pregnancy). Multivariable analyses were conducted using logistic regression. There were 5,372 pregnancies in the ART-naive group and 605 in the HAART-experienced group. Overall, there was weak evidence of an increased risk of detectable viral load in the HAART-experienced group (adjusted odds ratio [aOR] 1.27; 95% CI 1.01, 1.60); however, the increased risk was apparent only among women who previously received non-nucleoside reverse transcriptase inhibitor-based HAART (aOR 1.81; 95% CI 1.25, 2.63), and not among those with previous protease-inhibitor-based HAART exposure (aOR 1.08; 95% CI 0.81, 1.45). There was no difference in mother-to-child transmission risk between the ART-naive and HAART-experienced groups (aOR 0.42; 95% CI 0.10, 1.78), although the number of transmissions was small. We found no increased risk of detectable viral load at delivery among women exposed to short-course, protease-inhibitor-based HAART during a previous pregnancy. However, women with prior exposure to non-nucleoside reverse transcriptase inhibitor-based HAART appeared to be at increased risk of not adequately suppressing the virus. These findings highlight the need for careful management of HIV-infected women presenting with repeat pregnancies.

Short-Course Antiretroviral Therapy in Primary HIV Infection

BackgroundShort-course antiretroviral therapy (ART) in primary human immunodeficiency virus (HIV) infection may delay disease progression but has not been adequately evaluated.MethodsWe randomly assigned adults with primary HIV infection to ART for 48 weeks, ART for 12 weeks, or no ART (standard of care), with treatment initiated within 6 months after seroconversion. The primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation.ResultsA total of 366 participants (60% men) underwent randomization to 48-week ART (123 participants), 12-week ART (120), or standard care (123), with an average follow-up of 4.2 years. The primary end point was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and standard-care groups. The average hazard ratio was 0.63 (95% confidence interval [CI], 0.45 to 0.90; P=0.01) for 48-week ART as compared with standard care and was 0.93 (95% CI, 0.67 to 1.29; P=0.67) for 12-week ART as compared with standard care. The proportion of participants who had a CD4+ count of less than 350 cells per cubic millimeter was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the standard-care group. Corresponding values for long-term ART initiation were 22%, 21%, and 22%. The median time to the primary end point was 65 weeks (95% CI, 17 to 114) longer with 48-week ART than with standard care. Post hoc analysis identified a trend toward a greater interval between ART initiation and the primary end point the closer that ART was initiated to estimated seroconversion (P=0.09), and 48-week ART conferred a reduction in the HIV RNA level of 0.44 log10 copies per milliliter (95% CI, 0.25 to 0.64) 36 weeks after the completion of short-course therapy. There were no significant between-group differences in the incidence of the acquired immunodeficiency syndrome, death, or serious adverse events.ConclusionsA 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment. There was no evidence of adverse effects of ART interruption on the clinical outcome. (Funded by the Wellcome Trust; SPARTAC Controlled-Trials.com number, ISRCTN76742797, and EudraCT number, 2004-000446-20.)

Pregnant … pause? Is there a difference in the long‐term outcome of women starting ART for the first time in pregnancy?

Purpose of the studyThe guidelines on the initial choice of antiretroviral therapy (ART) in women starting ART for the first time in pregnancy have changed considerably over the past 13 years [1,2]. We sought to determine whether these different ART strategies have influenced subsequent clinical, immunological or virological outcomes in our population. Women in our cohort received either zidovudine (AZT) monotherapy, short course antiretroviral therapy (SCART) or continued ART post‐partum. AZT monotherapy in pregnancy was common a decade ago, but its use declined amidst concerns about efficacy and the potential development of resistance with monotherapy. SCART more effectively suppresses viral load (VL) but avoids unnecessary treatment post‐partum in those considered at low risk of disease progression. This is used less now the benefits of starting ART at better‐conserved CD4 counts and the risks of treatment interruption are known.Method30 women who commenced ART during a pregnancy which resulted in a live birth between 1999 and 2004 were identified from a departmental database. Women already on ART or who had previously received AZT monotherapy or SCART were excluded, as were women with less than 2 years follow up post‐partum. Outcomes included time to starting ART, CD4 count and VL on starting ART and at last follow up.Summary of results12 women received AZT monotherapy, 7 SCART and 11 continued ART post‐partum. In total there were 269 years of patient follow up (mean 9, range 2–13). (mean) AZT monotherapy SCART Continued ART Baseline CD4 409 359 190 Baseline VL 1,950 6,799 59,566 Time to starting ART 5.2 years* 4.6 years** CD4 on starting ART 254 178 CD4 &lt;350 on starting ART 3/12 3/7 CD4 at last follow up 519 451 543 1 still not on ART at last follow up; **2 not on ART at last follow up. None of the women who received AZT monotherapy or SCART experienced clinical disease progression during their time off therapy, which was considerable (mean 4–5 years). All achieved virological suppression and good CD4 recovery on commencing ART. None of the available genotypes in these patients showed resistance mutations. Of the women who continued ART, more than half modified their regimen and a significant number experienced transient VL rebounds.ConclusionsThe clinical choices made a decade ago do not appear to have been detrimental to the longer‐term treatment responses in this group of women. However, the effects of treatment interruption remain unclear and we suggest a cautious approach.

Impact of maternal HAART on the prevention of mother-to-child transmission of HIV: results of an 18-month follow-up study in Ouagadougou, Burkina Faso

Mother-to-child transmission remains the main cause of global pediatric HIV infections, especially in sub-Saharan Africa. Many interventions based on single-dose antiretroviral therapy have been implemented to reduce the mother-to-child transmission of HIV. In resource-limited settings, highly active antiretroviral therapy (HAART) has only been recommended for HIV-infected pregnant women requiring treatment for their own health. Here, we assessed the efficacy over 18 months of maternal HAART versus peripartum short-course antiretroviral therapy (SCART) regimens for the prevention of mother-to-child transmission (PMTCT) of HIV. We conducted a retrospective cohort study of patients from two medical centers in Ouagadougou, Burkina Faso. The PMTCT files and registers from 1 January 2003 to 31 December 2006 were obtained from routine data collected at these sites. The main assessment criterion was the rate of HIV-1 positivity in children born to HIV-positive mothers as measured with HIV-1 rapid tests at 18 months. A total of 586 pregnant HIV-1-infected women in PMTCT programs were selected. Among these women, 260 were undergoing HAART and 326 received single-dose nevirapine (91.3%) or single-dose zidovudine (8.7%) at delivery. HIV-1 serological tests were performed on 454 children at 18 months old. The rate of HIV-1 vertical transmission was 0% (0/195) in the HAART group and 4.6% (12/259) in the single-dose monotherapy group (P<0.01). Eight infants in the HAART cohort and 30 in the SCART cohort were breastfed; three in the SCART group were HIV-positive. A total of 62 children died, 19 in the HAART group and 43 in the single-dose monotherapy group. Our study confirms that HAART for mothers effectively reduces the risk of infant HIV infection while preserving the breastfeeding option for mothers.

Mothers, Midwives, and HIV/AIDS in Sub-Saharan Africa

This article reviews clinical and program issues in the prevention of mother to child transmission (PMTCT) of HIV in sub-Saharan Africa. Topics include prevention of infection, voluntary counseling and testing, prenatal care, labor and birth, postpartum, family planning, infant feeding, and the role of traditional birth attendants. Programs providing short-course antiretroviral therapy to prevent infant infection are contrasted with comprehensive programs offering antiretroviral therapy and medical care to mothers, children, and families. Feminization of the epidemic is related to gender inequalities that facilitate the spread of HIV and make pregnant women an especially vulnerable group. Nurses and midwives are the primary health care providers for most of the population in sub-Saharan Africa. They are the backbone of the new PMTCT programs and will be the largest group of health workers available to diagnose and treat opportunistic infections and dispense antiretroviral therapy. But they have received little training and support to provide AIDS care and treatment and are rarely consulted when plans are made about workforce issues and capacity development in the health sector. Clinical training, leadership skills, salary support, expansion of the nursing workforce, and development of expanded roles for nurses and midwives in AIDS care are needed to help them turn the tide of the epidemic.

Avoiding HIV and dying of syphilis

A mother in Haiti seeks prenatal care at a local health clinic, accepts HIV voluntary counselling and testing, and, after testing HIV-positive, takes short-course antiretroviral therapy for prevention of mother-to-child transmission (PMTCT). Postpartum, she gives her baby antiretroviral therapy and provides artificial milk to protect against HIV transmission through breastfeeding. Is this a success story for PMTCT? No, the baby died at 3 weeks from congenital syphilis. Is this an isolated case? No, we have seen several babies in Haiti who have died of congenital syphilis after completion of PMTCT.

Prospects of vaccination as a means of preventing mother-to-child transmission of HIV-I.

Although short-course antiretroviral therapy is efficient in reducing mother-to-child transmission (MTCT) of HIV-1, it does not prevent transmission during the breastfeeding period. There is therefore an urgent need to test various approaches, including HIV-1 vaccination, to try to prevent postnatal transmission of HIV-1 in breastfeeding populations in developing countries.

Viral levels in newborn African infants undergoing primary HIV-1 infection

We examined weekly changes in viral levels in seven untreated infants infected with HIV at birth. Viral levels spiked immediately but reverted quickly to plateau levels typical of infant HIV infection within 2 weeks of first detected viraemia. We speculated that the depletion of naive, susceptible cells is responsible for the rapid decrease in spike levels and that the rapid replacement of lymphocytes in infants causes the high plateau viral levels (10(5) copies/ml) to be sustained.

Partner notification by HIV-1 seropositive pregnant women: association with infant feeding decisions.

Many countries in sub-Saharan Africa are in the process of integrating antenatal voluntary HIV-1 counseling and testing (VCT), antiretroviral prophylaxis, and counseling regarding infant feeding into routine maternal and child health services.1 Even with greater availability of interventions to protect infants from HIV-1 acquisition, many women choose not to receive their HIV-1 test results, and many who learn that they are HIV infected do not implement interventions to prevent vertical or sexual transmission. In both research and non-research settings, <75% of HIV-infected pregnant women who are tested learn their HIV-1 status2,3 and <50% of these women obtain antiretrovirals to prevent mother-to-child HIV-1 transmission2,4–6 or use condoms postpartum.7,8 Not disclosing HIV-1 test results to a sexual partner may impede a woman’s access to interventions to prevent vertical and sexual HIV-1 transmission. There is evidence that lack of partner support is associated with poor uptake of antiretroviral medication and the inability to modify infant feeding practices.9,10 Sexual abstinence and condom use have also been shown to be more common among postpartum women who reveal HIV-positive results to partners.7 These associations between partner involvement and uptake of interventions underscore the importance of involving the male partner in HIV-1 prevention efforts initiated in the antenatal setting. Antenatal VCT involves counseling and testing the woman alone, with the expectation that she will disclose results to her partner. Using this model, the majority of pregnant women in stable relationships who are tested as part of routine care do not inform their partner of positive HIV-1 results, fearing domestic violence, abandonment, or stigmatization.7,11,12 We hypothesized that conducting VCT for pregnant women together with partners could facilitate notification and increase partner participation in the decision-making process. This could in turn improve maternal access to mother-to-child HIV-1 prevention interventions. Studies among discordant couples in nonantenatal settings support this hypothesis and demonstrate that couple counseling is associated with significant behavior change, including sustainable increases in condom use.13–15 In addition, when comparing couple counseling and individual counseling, provision of counseling to couples appears to be more cost-effective in averting HIV-1 infections.16 To examine whether couple counseling in the antenatal setting could be used as a strategy to increase use of interventions to prevent perinatal and sexual HIV-1 transmission, we introduced couple VCT into a Nairobi antenatal clinic and determined the prevalence and correlates of partner participation and couple counseling. The study’s primary aim was to assess the impact of partner involvement, specifically being counseled as a couple, on perinatal intervention uptake and condom use.