Anthony Ogwu

Publications (16)62.62 Total impact

• Article: No Clinically Significant Drug Resistance Mutations In HIV-1 subtype C Infected Women After Discontinuation Of NRTI-Based Or PI-Based HAART For PMTCT In Botswana.

  Sajini Souda, Simani Gaseitsiwe, Nathan Georgette, Kathleen Powis, Daisy Moremedi, Thato Iketleng, Jean Leidner, Claire Moffat, Anthony Ogwu, Shahin Lockman, Sikhulile Moyo, Mompati Mmalane, Rosemary Musonda, Joseph Makhema, Max Essex, Roger Shapiro
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  ABSTRACT: Risk of developing drug resistance after stopping antiretroviral regimens to prevent mother-to-child HIV-1 transmission (PMTCT) is unknown. Mma Bana Study randomized treatment-naïve pregnant women with CD4 ≥200 cells/mm to receive either abacavir/zidovudine/lamivudine (triple NRTI arm) or lopinavir/ritonavir/zidovudine/lamivudine (PI arm). Drugs were discontinued after 6 months breastfeeding. One month post-discontinuation, 29 NRTI arm samples and 25 PI arm samples were successfully genotyped. No clinically significant antiretroviral resistance mutations were detected. Eight minor resistance mutations were found among 11(20%) women (3 from NRTI arm, 8 from PI arm), occurring at similar frequencies to those reported in HIV-1 subtype C treatment naive cohorts.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 03/2013; · 4.43 Impact Factor
• Article: High Viral Load and Elevated Angiogenic Markers Associated with Increased Risk of Preeclampsia among Women Initiating Highly Active Antiretroviral Therapy (HAART) in Pregnancy in the Mma Bana Study, Botswana.

  Kathleen M Powis, Thomas F McElrath, Michael D Hughes, Anthony Ogwu, Sajini Souda, Saul A Datwyler, Erik von Widenfelt, Sikhulile Moyo, Marisa Nádas, Joseph Makhema, Esther Machakaire, Shahin Lockman, Max Essex, Roger L Shapiro
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  ABSTRACT: BACKGROUND:: Risk factors associated with preeclampsia in HIV-infected women remain largely unknown. Systemic angiogenic imbalance contributes to preeclampsia in HIV-uninfected women, but changes in angiogenic markers after HAART initiation have not been studied. METHODS:: The Mma Bana study randomized 560 HIV-infected, HAART-naive pregnant women with CD4 counts ≥ 200 cells/mmbetween 26-34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine or abacavir/zidovudine/lamivudine. Another 170 participants with CD4 counts < 200 cells/mm initiated nevirapine/zidovudine/lamivudine between 18-34 weeks gestation. Characteristics of 11 women who developed preeclampsia were compared with the remaining722 Mma Bana participants who delivered, using logistic regression. Plasma samples drawn at HAART initiation and one month later from 60 women without preeclampsia and at HAART initiation for all11 preeclamptic women were assayed for placental growth factor (PlGF) and soluble FMS toll-like tyrosine kinase-1 (sFlt-1) RESULTS:: Pre-HAART viral load > 100,000 copies/ml was associated with preeclampsia (OR 5.8; 95% CI 1.8, 19.4; p = 0.004). Median pre-HAART PlGF level was lower and sFLT-1 was higher in women who developed preeclampsia versus those who did not (130 vs 992 pg/ml, p=0.001; 17.5 vs 9.4 pg/ml, p=0.03, respectively). In multivariate analysis, PlGF and viral load remained significantly associated with preeclampsia. No significant changes in angiogenic factors were noted after 1 month of HAART treatment among non-preeclamptic women. CONCLUSIONS:: Pre-HAART viral load > 100,000 copies/ml and PlGF predicted preeclampsia among women starting HAART in pregnancy. Among non-preeclamptic women, HAART treatment did not significantly alter levels of PlGF or sFlt-1 on month into treatment.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2013; · 4.43 Impact Factor
• Article: Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast milk, in the Mma Bana Study, Botswana.

  Roger L Shapiro, Steven Rossi, Anthony Ogwu, Mary Moss, Jean Leidner, Claire Moffat, Shahin Lockman, Sikhulile Moyo, Joseph Makhema, Max Essex, Edmund Capparelli
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  ABSTRACT: BACKGROUND: Pharmacokinetic data for lopinavir in late pregnancy and in breastfeeding are limited, and no data for abacavir in breast milk are available. METHODS: Women in the Mma Bana Study initiated highly active antiretroviral therapy (HAART) from 18-34 weeks' gestation. We determined trough plasma and whole breast milk concentrations of lopinavir (LPV), abacavir (ABC), nevirapine (NVP), lamivudine (3TC), and zidovudine (ZDV) among separate subsets of pregnant and breastfeeding women, and in plasma of exposed infants. Lopinavir was measured 1 month after starting HAART or 1 month postpartum, and other drugs were measured 1 month postpartum. RESULTS: Sampling occurred a median of 14 hours (range 11-17 hours) from last maternal drug ingestion. Although 50% higher median LPV levels were seen in postpartum than antepartum plasma (8.29 ug/mL vs. 5.51 ug/mL, p=0.02), antepartum levels with standard LPV dosing were therapeutic for all women (> 1.0 ug/mL). Very low LPV levels (< 0.25 ug/mL) were detected in breast milk. Median ABC levels in breast milk were 85% of plasma (0.057 ug/mL vs. 0.067 ug/mL). Breast milk concentrations of NVP and 3TC were 0.27 and 0.74 of plasma levels, respectively. At these trough maternal time points, only NVP was detectable in potentially inhibitory levels in breastfeeding infants, and most infants had non-detectable levels of LPV, ABC, ZDV and 3TC via maternal breast milk. CONCLUSIONS: Standard lopinavir dosing achieved therapuetic levels in pregnancy and no appreciable concentrations in breast milk. ABC is detectable in breast milk at similar concentrations to plasma, but does not result in appreciable infant exposure.
  Antiviral therapy 11/2012; · 3.16 Impact Factor
• Article: Highly Active Antiretroviral Therapy and Adverse Birth Outcomes Among HIV-Infected Women in Botswana.

  Jennifer Y Chen, Heather J Ribaudo, Sajini Souda, Natasha Parekh, Anthony Ogwu, Shahin Lockman, Kathleen Powis, Scott Dryden-Peterson, Tracy Creek, William Jimbo, Tebogo Madidimalo, Joseph Makhema, Max Essex, Roger L Shapiro
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  ABSTRACT: Background. It is unknown whether adverse birth outcomes are associated with maternal highly active antiretroviral therapy (HAART) in pregnancy, particularly in resource-limited settings.Methods. We abstracted obstetrical records at 6 sites in Botswana for 24 months. Outcomes included stillbirths (SBs), preterm delivery (PTD), small for gestational age (SGA), and neonatal death (NND). Among human immunodeficiency virus (HIV)-infected women, comparisons were limited to HAART exposure status at conception, and those with similar opportunities for outcomes. Comparisons were adjusted for CD4(+) lymphocyte cell count.Results. Of 33 148 women, 32 113 (97%) were tested for HIV, of whom 9504 (30%) were HIV infected. Maternal HIV was significantly associated with SB, PTD, SGA, and NND. Compared with all other HIV-infected women, those continuing HAART from before pregnancy had higher odds of PTD (adjusted odds ratio [AOR], 1.2; 95% confidence interval [CI], 1.1, 1.4), SGA (AOR, 1.8; 95% CI, 1.6, 2.1) and SB (AOR, 1.5; 95% CI, 1.2, 1.8). Among women initiating antiretroviral therapy in pregnancy, HAART use (vs zidovudine) was associated with higher odds of PTD (AOR, 1.4; 95% CI, 1.2, 1.8), SGA (AOR, 1.5; 95% CI, 1.2, 1.9), and SB (AOR, 2.5; 95% CI, 1.6, 3.9). Low CD4(+) was independently associated with SB and SGA, and maternal hypertension during pregnancy with PTD, SGA, and SB.Conclusions. HAART receipt during pregnancy was associated with increased PTD, SGA, and SB.
  The Journal of Infectious Diseases 10/2012; · 6.41 Impact Factor
• Article: Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope.

  Philippa C Matthews, Madoka Koyanagi, Henrik N Kløverpris, Mikkel Harndahl, Anette Stryhn, Tomohiro Akahoshi, Hiroyuki Gatanaga, Shinichi Oka, Claudia Juarez Molina, Humberto Valenzuela Ponce, [......], Roger Shapiro, Christian Brander, Bruce Walker, Andrew K Sewell, Gustavo Reyes Teran, David Heckerman, Eric Hunter, Søren Buus, Masafumi Takiguchi, Philip J R Goulder
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  ABSTRACT: The strongest genetic influence on immune control in HIV-1 infection is HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes, but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrate that, whereas HLA-B*3501 is associated with high viral setpoint in two further B-clade infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8+ T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope, NPPIPVGDIY ('NY10' , Gag 253-262, p=2×10(-5)). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response towards NY10 was associated with a significantly lower viral setpoint. Non-immunogenicity of NY10 in B-clade infected subjects derives from the Gag-D260E polymorphism present in ∼90% of B-clade sequences, which critically reduces recognition of the Gag-NY10 epitope. These data suggest that, in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8+ T-cell response, by the addition of even a single epitope, may be of over-riding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8+ T-cell response in all individuals, irrespective of HLA type.
  Journal of Virology 09/2012; · 5.40 Impact Factor
• Article: Abacavir alters the transcription of inflammatory cytokines in virologically suppressed, HIV-infected women.

  Iain J MacLeod, Christopher F Rowley, Shahin Lockman, Anthony Ogwu, Sikhulile Moyo, Erik van Widenfelt, Mompati Mmalane, Joseph Makhema, M Essex, Roger L Shapiro
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  ABSTRACT: Abacavir (ABC) may be associated with a small, increased risk of myocardial infarction in HIV-infected adults, possibly related to cytokine-mediated inflammation. To evaluate the induction of inflammatory cytokine transcription by ABC, we used samples from women randomized to receive zidovudine/lamivudine/ABC (Trizivir) or lopinavir/ritonavir and zidovudine/lamividine (Kaletra/Combivir) from the third trimester through six-months postpartum for the prevention of mother-to-child transmission (PMTCT). Women were matched by CD4 count and baseline HIV RNA. All women attained viral suppression (<50 copies/ml) by the time of sampling. Four cytokines showed a difference in expression between the treatment arms, all in a proinflammatory direction for the ABC arm: CD40LG 1.82-fold, (p=.027); IL-8 3.16-fold (p=.020); LTA 2.82-fold, (p=.008); and CCL5 -1.67-fold, (p=.035). At 12-months postpartum, 6-months after antiretroviral discontinuation, cytokine expression was similar by treatment arm. We conclude that ABC may upregulate proinflammatory cytokines at the transcriptional level in this population.
  Journal of the International AIDS Society 01/2012; 15(2):17393. · 3.26 Impact Factor
• Article: Co-Operative Additive Effects between HLA Alleles in Control of HIV-1.

  Philippa C Matthews, Jennifer Listgarten, Jonathan M Carlson, Rebecca Payne, Kuan-Hsiang Gary Huang, John Frater, Dominique Goedhals, Dewald Steyn, Cloete van Vuuren, Paolo Paioni, Pieter Jooste, Anthony Ogwu, Roger Shapiro, Zenele Mncube, Thumbi Ndung'u, Bruce D Walker, David Heckerman, Philip J R Goulder
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  ABSTRACT: HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles - irrespective of linkage disequilibrium - function co-operatively. We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate 'co-operative additive' effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel 'sharing score' to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03). These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect.
  PLoS ONE 01/2012; 7(10):e47799. · 4.09 Impact Factor
• Source

  Available from: PubMed Central

  Article: Birth weight for gestational age norms for a large cohort of infants born to HIV-negative women in Botswana compared with norms for U.S.-born black infants.

  Lynn T Matthews, Heather J Ribaudo, Natasha K Parekh, Jennifer Y Chen, Kelebogile Binda, Anthony Ogwu, Joseph Makhema, Sajini Souda, Shahin Lockman, Max Essex, Roger L Shapiro
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  ABSTRACT: Standard values for birth weight by gestational age are not available for sub-Saharan Africa, but are needed to evaluate incidence and risk factors for intrauterine growth retardation in settings where HIV, antiretrovirals, and other in utero exposures may impact birth outcomes. Birth weight data were collected from six hospitals in Botswana. Infants born to HIV-negative women between 26-44 weeks gestation were analyzed to construct birth weight for gestational age charts. These data were compared with published norms for black infants in the United States. During a 29 month period from 2007-2010, birth records were reviewed in real-time from 6 hospitals and clinics in Botswana. Of these, 11,753 live infants born to HIV-negative women were included in the analysis. The median gestational age at birth was 39 weeks (1st quartile 38, 3rd quartile 40 weeks), and the median birth weight was 3100 grams (1st quartile 2800, 3rd quartile 3400 grams). We constructed estimated percentile curves for birth weight by gestational age which demonstrate increasing slope during the third trimester and leveling off beyond 40 weeks. Compared with black infants in the United States, Botswana-born infants had lower median birth weight for gestational age from weeks 37 through 42 (p < .02). We present birth weight for gestational age norms for Botswana, which are lower at term than norms for black infants in the United States. These findings suggest the importance of regional birth weight norms to identify and define risk factors for higher risk births. These data serve as a reference for Botswana, may apply to southern Africa, and may help to identify infants at risk for perinatal complications and inform comparisons among infants exposed to HIV and antiretrovirals in utero.
  BMC Pediatrics 12/2011; 11:115. · 1.88 Impact Factor
• Article: Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy.

  Kathleen M Powis, Douglas Kitch, Anthony Ogwu, Michael D Hughes, Shahin Lockman, Jean Leidner, Erik van Widenfelt, Claire Moffat, Sikhulile Moyo, Joseph Makhema, Max Essex, Roger L Shapiro
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  ABSTRACT: Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies. HIV-infected, HAART-naive pregnant women with CD4+ counts ≥200 cells/mm(3) were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother-to-child HIV transmission. Risk factors for preterm delivery (<37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression. Preterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26-3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen. PI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study.
  The Journal of Infectious Diseases 08/2011; 204(4):506-14. · 6.41 Impact Factor
• Article: HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703.

  Philippa C Matthews, Emily Adland, Jennifer Listgarten, Alasdair Leslie, Nompumelelo Mkhwanazi, Jonathan M Carlson, Mikkel Harndahl, Anette Stryhn, Rebecca P Payne, Anthony Ogwu, [......], Lynn Riddell, Fabian Chen, Graz Luzzi, Thambiah Balachandran, Thumbi Ndung'u, Søren Buus, Mary Carrington, Roger Shapiro, David Heckerman, Philip J R Goulder
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  ABSTRACT: The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.
  The Journal of Immunology 05/2011; 186(10):5675-86. · 5.79 Impact Factor
• Article: Effects of in utero antiretroviral exposure on longitudinal growth of HIV-exposed uninfected infants in Botswana.

  Kathleen M Powis, Laura Smeaton, Anthony Ogwu, Shahin Lockman, Scott Dryden-Peterson, Erik van Widenfelt, Jean Leidner, Joseph Makhema, Max Essex, Roger L Shapiro
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  ABSTRACT: The impact of in utero exposure to highly active antiretroviral therapy (HAART) on longitudinal growth of HIV-uninfected infants is unknown. The Mashi and Mma Bana PMTCT intervention trials enrolled HIV-infected pregnant women at four sites in Botswana. Breast-fed (BF), HIV-uninfected infants born at 37 weeks or greater were included in this analysis. Weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) z-scores were calculated using World Health Organization Child Growth Standards. Mean z-scores were compared between in utero antiretroviral exposure groups using Student t test, response profiles analysis, and general linear mixed effects modeling. Growth of 619 HAART-exposed and 440 zidovudine-exposed, HIV-uninfected infants was evaluated. Mean birth weights were 3.01 kg for HAART and 3.15 kg for zidovudine-exposed infants (P < 0.001) with lower mean birth WAZ, length-for-age (LAZ), and weight-for-length (WLZ) among HAART-exposed infants (all P < 0.001). HAART-exposed infants had greater improvement in WAZ and weight-for-length (WLZ) from birth through 2 months (P = 0.03, P < 0.001, respectively). The WAZ did not differ between groups from 3 through 6 months (P = 0.26). Length-for-age (LAZ) remained lower in HAART-exposed infants but the incidence of wasting or stunting did not differ between exposure groups. Lower weights in HAART-exposed uninfected infants at birth were rapidly corrected during the first 6 months of life.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2011; 56(2):131-8. · 4.43 Impact Factor
• Article: Increased risk of severe infant anemia after exposure to maternal HAART, Botswana.

  Scott Dryden-Peterson, Roger L Shapiro, Michael D Hughes, Kathleen Powis, Anthony Ogwu, Claire Moffat, Sikhulile Moyo, Joseph Makhema, Max Essex, Shahin Lockman
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  ABSTRACT: Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission but may increase the risk for infant anemia. The incidence of first severe anemia (grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana mother-to-child HIV transmission prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding (BF) and 1 month of postnatal zidovudine (ZDV) (HAART-BF); infants exposed to maternal ZDV in utero, 6 months of postnatal ZDV, and BF (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF). A total of 1719 infants were analyzed-691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P < 0.001) and 2.5% of ZDV-FF infants (P < 0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia. Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2011; 56(5):428-36. · 4.43 Impact Factor
• Source

  Available from: Sikhulile Moyo

  Article: HIV-1 subtype C-infected individuals maintaining high viral load as potential targets for the "test-and-treat" approach to reduce HIV transmission.

  Vladimir Novitsky, Rui Wang, Hermann Bussmann, Shahin Lockman, Marianna Baum, Roger Shapiro, Ibou Thior, Carolyn Wester, C William Wester, Anthony Ogwu, [......], Erik van Widenfelt, Madisa Mine, Claire Moffat, Mompati Mmalane, Joseph Makhema, Richard Marlink, Peter Gilbert, George R Seage, Victor DeGruttola, M Essex
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  ABSTRACT: The first aim of the study is to assess the distribution of HIV-1 RNA levels in subtype C infection. Among 4,348 drug-naïve HIV-positive individuals participating in clinical studies in Botswana, the median baseline plasma HIV-1 RNA levels differed between the general population cohorts (4.1-4.2 log(10)) and cART-initiating cohorts (5.1-5.3 log(10)) by about one log(10). The proportion of individuals with high (> or = 50,000 (4.7 log(10)) copies/ml) HIV-1 RNA levels ranged from 24%-28% in the general HIV-positive population cohorts to 65%-83% in cART-initiating cohorts. The second aim is to estimate the proportion of individuals who maintain high HIV-1 RNA levels for an extended time and the duration of this period. For this analysis, we estimate the proportion of individuals who could be identified by repeated 6- vs. 12-month-interval HIV testing, as well as the potential reduction of HIV transmission time that can be achieved by testing and ARV treating. Longitudinal analysis of 42 seroconverters revealed that 33% (95% CI: 20%-50%) of individuals maintain high HIV-1 RNA levels for at least 180 days post seroconversion (p/s) and the median duration of high viral load period was 350 (269; 428) days p/s. We found that it would be possible to identify all HIV-infected individuals with viral load > or = 50,000 (4.7 log(10)) copies/ml using repeated six-month-interval HIV testing. Assuming individuals with high viral load initiate cART after being identified, the period of high transmissibility due to high viral load can potentially be reduced by 77% (95% CI: 71%-82%). Therefore, if HIV-infected individuals maintaining high levels of plasma HIV-1 RNA for extended period of time contribute disproportionally to HIV transmission, a modified "test-and-treat" strategy targeting such individuals by repeated HIV testing (followed by initiation of cART) might be a useful public health strategy for mitigating the HIV epidemic in some communities.
  PLoS ONE 01/2010; 5(4):e10148. · 4.09 Impact Factor
• Article: Antiretroviral treatment initiation among HIV-infected pregnant women with low CD4(+) cell counts in Gaborone, Botswana.

  Jennifer Y Chen, Anthony C Ogwu, Petr Svab, Shahin Lockman, Howard J Moffat, Tendani Gaolathe, Shana Moilwa, Ketil Størdal, Scott Dryden-Peterson, Claire Moffat, Joseph Makhema, M Essex, Roger L Shapiro
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  ABSTRACT: Botswana has the most comprehensive public program in Africa for providing antiretroviral therapy to treat HIV and prevent mother-to-child transmission (PMTCT). Botswana guidelines prioritize CD4(+) cell count testing during pregnancy and initiation of highly active antiretroviral treatment (HAART) for women who qualify for treatment. We analyzed rates of HIV testing, CD4 cell count testing, and HAART initiation during pregnancy. From October 2007 through June 2008, we reviewed obstetric and laboratory records of women at Princess Marina Hospital in Gaborone, Botswana. We recorded information from 3056 women. Of 2675 women eligible for the PMTCT program, 2623 (98%) had a documented HIV status, of whom 793 (30%) were HIV infected. Among women who were treatment naive at pregnancy conception, 397 (59%) had recorded CD4(+) cell counts, of whom 62 (16%) had a CD4(+) cell count <200 cells per cubic millimeter. Among this subset, 23 (37%) initiated HAART during pregnancy, 26 (42%) received zidovudine prophylaxis, and 13 (21%) received no therapy. We observed low rates of CD4(+) cell count testing and HAART initiation during pregnancy. Antenatal clinics should prioritize CD4(+) cell count testing and referral of women who qualify for HAART to maximize benefits of maternal treatment and PMTCT.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 10/2009; 54(1):102-6. · 4.43 Impact Factor
• Article: Adaptation of HIV-1 to human leukocyte antigen class I

  Yuka Kawashima, Katja Pfafferott, John Frater, Philippa Matthews, Rebecca Payne, Marylyn Addo, Hiroyuki Gatanaga, Mamoru Fujiwara, Atsuko Hachiya, Hirokazu Koizumi, [......], Jonathan Weber, Oliver G Pybus, Paul Klenerman, Thumbi Ndung'u, Rodney Phillips, David Heckerman, P Richard Harrigan, Bruce D Walker, Masafumi Takiguchi, Philip Goulder
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  ABSTRACT: The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host-pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8(+) T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection. Mutation within these epitopes can allow viral escape from CD8(+) T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128-135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P
  Nature. 458(7238):641-645.
• Article: HIV-1 Subtype C-Infected Individuals Maintaining High Viral Load as Potential Targets for the “Test-and-Treat” Approach to Reduce HIV Transmission

  Marianna Baum, Ibou Thior, Aida Asmelash, Adriana Campa, Erik van Widenfelt, Madisa Mine, Claire Moffat, Mompati Mmalane, Peter Gilbert, Vladimir A. Novitsky, [......], Carolyn Negley Wester, C William Wester, Anthony Ogwu, Rosemary Mubanga Musonda, Sikhulile Moyo, Joseph Moeketsi Makhema, Richard George Marlink, George R Seage, Victor Gerard De Gruttola, Myron Elmer Essex
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  ABSTRACT: The first aim of the study is to assess the distribution of HIV-1 RNA levels in subtype C infection. Among 4,348 drug-naïve HIV-positive individuals participating in clinical studies in Botswana, the median baseline plasma HIV-1 RNA levels differed between the general population cohorts (4.1–4.2 log10) and cART-initiating cohorts (5.1–5.3 log10) by about one log10. The proportion of individuals with high (≥50,000 (4.7 log10) copies/ml) HIV-1 RNA levels ranged from 24%–28% in the general HIV-positive population cohorts to 65%–83% in cART-initiating cohorts. The second aim is to estimate the proportion of individuals who maintain high HIV-1 RNA levels for an extended time and the duration of this period. For this analysis, we estimate the proportion of individuals who could be identified by repeated 6- vs. 12-month-interval HIV testing, as well as the potential reduction of HIV transmission time that can be achieved by testing and ARV treating. Longitudinal analysis of 42 seroconverters revealed that 33% (95% CI: 20%–50%) of individuals maintain high HIV-1 RNA levels for at least 180 days post seroconversion (p/s) and the median duration of high viral load period was 350 (269; 428) days p/s. We found that it would be possible to identify all HIV-infected individuals with viral load ≥50,000 (4.7 log10) copies/ml using repeated six-month-interval HIV testing. Assuming individuals with high viral load initiate cART after being identified, the period of high transmissibility due to high viral load can potentially be reduced by 77% (95% CI: 71%–82%). Therefore, if HIV-infected individuals maintaining high levels of plasma HIV-1 RNA for extended period of time contribute disproportionally to HIV transmission, a modified “test-and-treat” strategy targeting such individuals by repeated HIV testing (followed by initiation of cART) might be a useful public health strategy for mitigating the HIV epidemic in some communities.