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1.  Emergence of HIV Drug Resistance During First- and Second-Line Antiretroviral Therapy in Resource-Limited Settings 
The Journal of Infectious Diseases  2013;207(Suppl 2):S49-S56.
Antiretroviral therapy (ART) in resource-limited settings has expanded in the last decade, reaching >8 million individuals and reducing AIDS mortality and morbidity. Continued success of ART programs will require understanding the emergence of HIV drug resistance patterns among individuals in whom treatment has failed and managing ART from both an individual and public health perspective. We review data on the emergence of HIV drug resistance among individuals in whom first-line therapy has failed and clinical and resistance outcomes of those receiving second-line therapy in resource-limited settings.
Resistance surveys among patients initiating first-line nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based therapy suggest that 76%–90% of living patients achieve HIV RNA suppression by 12 months after ART initiation. Among patients with detectable HIV RNA at 12 months, HIV drug resistance, primarily due to M184V and NNRTI mutations, has been identified in 60%–72%, although the antiretroviral activity of proposed second-line regimens has been preserved. Complex mutation patterns, including thymidine-analog mutations, K65R, and multinucleoside mutations, are prevalent among cases of treatment failure identified by clinical or immunologic methods. Approximately 22% of patients receiving second-line therapy do not achieve HIV RNA suppression by 6 months, with poor adherence, rather than HIV drug resistance, driving most failures. Major protease inhibitor resistance at the time of second-line failure ranges from 0% to 50%, but studies are limited.
Resistance of HIV to first-line therapy is predictable at 12 months when evaluated by means of HIV RNA monitoring and, when detected, largely preserves second-line therapy options. Optimizing adherence, performing resistance surveillance, and improving treatment monitoring are critical for long-term prevention of drug resistance.
PMCID: PMC3708738  PMID: 23687289
antiretroviral drug resistance; resource-limited settings; second-line therapy
2.  The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy 
AIDS (London, England)  2009;23(9):1127-1134.
Over 150 000 Malawians have started antiretroviral therapy (ART), in which first-line therapy is stavudine/lamivudine/nevirapine. We evaluated drug resistance patterns among patients failing first-line ART on the basis of clinical or immunological criteria in Lilongwe and Blantyre, Malawi.
Patients meeting the definition of ART failure (new or progressive stage 4 condition, CD4 cell count decline more than 30%, CD4 cell count less than that before treatment) from January 2006 to July 2007 were evaluated. Among those with HIV RNA of more than 1000 copies/ml, genotyping was performed. For complex genotype patterns, phenotyping was performed.
Ninety-six confirmed ART failure patients were identified. Median (interquartile range) CD4 cell count, log10 HIV-1 RNA, and duration on ART were 68 cells/μl (23–174), 4.72 copies/ml (4.26–5.16), and 36.5 months (26.6–49.8), respectively. Ninety-three percent of samples had nonnucleoside reverse transcriptase inhibitor mutations, and 81% had the M184V mutation. The most frequent pattern included M184V and nonnucleoside reverse transcriptase inhibitor mutations along with at least one thymidine analog mutation (56%). Twenty-three percent of patients acquired the K70E or K65R mutations associated with tenofovir resistance; 17% of the patients had pan-nucleoside resistance that corresponded to K65R or K70E and additional resistance mutations, most commonly the 151 complex. Emergence of the K65R and K70E mutations was associated with CD4 cell count of less than 100 cells/μl (odds ratio 6.1) and inversely with the use of zidovudine (odds ratio 0.18). Phenotypic susceptibility data indicated that the nucleoside reverse transcriptase inhibitor backbone with the highest activity for subsequent therapy was zidovudine/lamivudine/tenofovir, followed by lamivudine/tenofovir, and then abacavir/didanosine.
When clinical and CD4 cell count criteria are used to monitor first-line ART failure, extensive nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance emerges, with most patients having resistance profiles that markedly compromise the activity of second-line ART.
PMCID: PMC2896488  PMID: 19417582
Africa; antiretroviral failure; public health approach; resistance; resource-limited setting
3.  Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post partum: results of the BAN Study 
Antiviral therapy  2014;19(6):587-595.
An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral, and Nutrition study was performed to describe drug exposure and antiviral response.
Women using Combivir®[zidovudine (ZDV)+ lamivudine (3TC)]+Aluvia®[lopinavir/ritonavir(LPV/RTV)] were enrolled. Breast milk (BM) and mother and infant plasma (MP, IP) samples were obtained over 6hrs after observed dosing at 6, 12, or 24wks post-partum for drug concentrations and HIV RNA.
30 mother/infant pairs (10 each at 6, 12,and 24wks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, while LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24wks. The majority (98.3%) of BM concentrations were >HIVwt IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA.
ZDV and 3TC concentrated in BM while LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low ARV concentrations in IP suggests prevention of transmission while breast feeding may be due to ARV effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early.
PMCID: PMC4110187  PMID: 24464632
4.  Medical eligibility, contraceptive choice, and intrauterine device acceptance among HIV-infected women receiving antiretroviral therapy in Lilongwe, Malawi 
To determine medical eligibility for contraceptive use, contraceptive preference, and acceptance of a copper intrauterine device (IUD) among a cohort of HIV-infected women receiving antiretroviral therapy (ART).
All HIV-infected women who received ART and sought contraceptive services at the Lighthouse clinic, an integrated HIV/ART clinic in Lilongwe, Malawi, between August and December 2010 were invited to participate in a structured interview. Eligibility and preference for the following contraceptive methods were assessed: combined hormonal contraceptives, progestogen-only pills, copper IUD, injectable depot medroxyprogesterone acetate (DMPA), and contraceptive implants.
The final sample included 281 women; five were pregnant. The remaining 276 women were eligible for at least three contraceptive methods, with 242 (87.7%) eligible for all five methods evaluated. After counseling, 163 (58.0%) selected DMPA and 98 (34.9%) selected an IUD as their preferred contraceptive method. Regardless of their method of choice, 222 (79.0%) women agreed to have an IUD placed on the same day.
Most methods of contraception are safe for use by HIV-infected women. Approximately 80% of the women were willing to receive an IUD. Efforts must be made to increase education about, and access to, long-acting reversible methods that may be acceptable and appropriate contraceptive options for HIV-infected women.
PMCID: PMC4149777  PMID: 24890746
Antiretroviral therapy; Contraception; HIV; Intrauterine contraception; Intrauterine device; Malawi; Medical eligibility
5.  Undisclosed Antiretroviral Drug Use in a Multinational Clinical Trial (HIV Prevention Trials Network 052) 
The Journal of Infectious Diseases  2013;208(10):1624-1628.
The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.
PMCID: PMC3805242  PMID: 23908493
HIV; antiretroviral drug; self-report; HPTN 052; Africa; clinical trial
6.  Viral Profiling Identifies Multiple Subtypes of Kaposi’s Sarcoma 
mBio  2014;5(5):e01633-14.
Kaposi’s sarcoma (KS), caused by KS-associated herpesvirus (KSHV), is the most common cancer among HIV-infected patients in Malawi and in the United States today. In Malawi, KSHV is endemic. We conducted a cross-sectional study of patients with HIV infection and KS with no history of chemo- or antiretroviral therapy (ART). Seventy patients were enrolled. Eighty-one percent had T1 (advanced) KS. Median CD4 and HIV RNA levels were 181 cells/mm3 and 138,641 copies/ml, respectively. We had complete information and suitable plasma and biopsy samples for 66 patients. For 59/66 (89%) patients, a detectable KSHV load was found in plasma (median, 2,291 copies/ml; interquartile range [IQR], 741 to 5,623). We utilized a novel KSHV real-time quantitative PCR (qPCR) array with multiple primers per open reading frame to examine KSHV transcription. Seventeen samples exhibited only minimal levels of KSHV mRNAs, presumably due to the limited number of infected cells. For all other biopsy samples, the viral latency locus (LANA, vCyc, vFLIP, kaposin, and microRNAs [miRNAs]) was transcribed abundantly, as was K15 mRNA. We could identify two subtypes of treatment-naive KS: lesions that transcribed viral RNAs across the length of the viral genome and lesions that displayed only limited transcription restricted to the latency locus. This finding demonstrates for the first time the existence of multiple subtypes of KS lesions in HIV- and KS-treatment naive patients.
KS is the leading cancer in people infected with HIV worldwide and is causally linked to KSHV infection. Using viral transcription profiling, we have demonstrated the existence of multiple subtypes of KS lesions for the first time in HIV- and KS-treatment-naive patients. A substantial number of lesions transcribe mRNAs which encode the viral kinases and hence could be targeted by the antiviral drugs ganciclovir or AZT in addition to chemotherapy.
PMCID: PMC4173763  PMID: 25249280
7.  Routine Inpatient HIV Testing System Increases Access to Pediatric HIV Care in sub-Saharan Africa 
Routine HIV testing, called provider-initiated opt-out HIV testing and counseling (PITC), is recommended in African countries with high HIV prevalence. However, it is unknown whether PITC increases access to pediatric HIV care. In 2008 the Baylor International Pediatric AIDS Initiative implemented PITC (BIPAI-PITC) at a Malawian hospital. We sought to evaluate the influence of BIPAI-PITC, compared to non-routine HIV testing (NRT), on pediatric HIV care access.
Retrospective data from 7,077 pediatric inpatients were collected during sequential four-month periods of NRT and BIPAI-PITC. In-hospital and one-year outcomes for 337 HIV-infected and HIV-exposed uninfected inpatients not previously enrolled in HIV care were analyzed to assess the clinical influence of each testing strategy.
During BIPAI-PITC, a greater proportion of all hospitalized children received HIV testing (81.0% vs 33.3%, p < 0.001), accessed inpatient HIV-trained care (7.5% vs 2.4%, p < 0.001), enrolled into an outpatient HIV clinic after discharge (3.2% vs 1.3%, p < 0.001), and initiated antiretroviral therapy (ART) following hospitalization (1.1% vs 0.6%, p = 0.010) compared to NRT. Additionally, BIPAI-PITC increased the proportion of hospitalized HIV-infected and HIV-exposed uninfected children receiving DNA PCR testing (73.5% vs 35.2%, p < 0.001), but did not improve outpatient enrollment or ART initiation of identified HIV-infected patients.
BIPAI-PITC increases access to inpatient and outpatient pediatric HIV care for hospitalized children, including DNA PCR testing and ART. Broader implementation of BIPAI-PITC or similar approaches, along with more pediatric HIV-trained clinicians and improved defaulter-tracking methods, would improve pediatric HIV service utilization globally.
PMCID: PMC4157210  PMID: 21297520
Pediatric HIV; Routine HIV Testing; Provider Initiated HIV Testing and Counseling; Early Infant Diagnosis; Africa South of the Sahara
8.  Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial 
The Lancet. Infectious diseases  2014;14(4):281-290.
Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes.
The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with, number NCT00074581.
1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373–522) cells per μL in patients assigned to the early treatment group and 428 (357–522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197–249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52–1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43–0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28–0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5–27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5–32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group.
Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment.
US National Institute of Allergy and Infectious Diseases.
PMCID: PMC4144040  PMID: 24602844
9.  Task-shifting an inpatient triage, assessment, and treatment program improves the quality of care for hospitalized Malawian children 
We aimed to improve pediatric inpatient surveillance at a busy referral hospital in Malawi with 2 new programs: (1) the provision of vital sign equipment and implementation of an inpatient triage program (ITAT) that includes a simplified pediatric severity-of-illness score; (2) task-shifting ITAT to a new cadre of health care workers called “Vital Sign Assistants” (VSAs).
This study, conducted on the pediatric inpatient ward of a large referral hospital in Malawi, was divided into 3 phases, each lasting 4 weeks. In Phase A, we collected baseline data. In Phase B, we provided 3 new automated vital sign poles and implemented ITAT with current hospital staff. In Phase C, VSAs were introduced and performed ITAT. Our primary outcome measures were the number of vital sign assessments performed and clinician notifications to reassess patients with high ITAT scores.
We enrolled 3,994 patients who received 5,155 vital sign assessments. Assessment frequency was equal between Phases A (0.67 assessments/patient) and B (0.61 assessments/patient), but increased 3.6-fold in Phase C (2.44 assessments/patient, p<0.001). Clinician notifications increased from Phases A (84) and B (113) to Phase C (161, p=0.002). Inpatient mortality fell from Phase A (9.3%) to Phases B (5.7) and C (6.9%).
ITAT with VSAs improved vital sign assessments and nearly doubled clinician notifications of patients needing further assessment due to high ITAT scores, while equipment alone made no difference. Task-shifting ITAT to VSAs may improve outcomes in pediatric hospitals in the developing world.
PMCID: PMC3683117  PMID: 23600592
pulse oximetry; pediatric early warning score; task-shift; Malawi; ITAT; vital sign
10.  Development of a severity of illness scoring system (ITAT) for resource-constrained hospitals in developing countries 
To develop a new pediatric illness severity score, called Inpatient Triage, Assessment, and Treatment (ITAT), for resource-limited settings to identify hospitalized patients at highest risk of death and facilitate urgent clinical re-evaluation.
We performed a nested case-control study at a Malawian referral hospital. The ITAT score was derived from 4 equally-weighted variables, yielding a cumulative score between 0 and 8. Variables included oxygen saturation, temperature, and age-adjusted heart and respiratory rates. We compared the ITAT score between cases (deaths) and controls (discharges) in predicting death within 2 days. Our analysis includes predictive statistics, bivariable and multivariable logistic regression, and calculation of data-driven scores.
A total of 54 cases and 161 controls were included in the analysis. The area under the receiver operating characteristic curve was 0.76. At an ITAT cutoff of 4, the sensitivity, specificity, and likelihood ratio were 0.44, 0.86, and 1.70, respectively. A cumulative ITAT score of 4 or higher was associated with increased odds of death (OR: 4.80; 95% CI: 2.39 – 9.64). A score of 2 for all individual vital signs was a statistically significant independent predictor of death.
We developed an inpatient triage tool (ITAT) appropriate for resource-constrained hospitals that identifies high-risk children after hospital admission. Further research is needed to study how best to operationalize ITAT in developing countries.
PMCID: PMC3713504  PMID: 23758198
vital sign; early warning score; PEWS; pediatric; Malawi; ITAT
11.  Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine 
The Journal of Infectious Diseases  2013;207(Suppl 2):S70-S77.
The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure.
We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance.
Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M.
Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.
PMCID: PMC3657117  PMID: 23687292
HIV-1; drug resistance; mutations; nucleoside reverse transcriptase inhibitor; NRTI; stavudine; d4T; zidovudine; AZT; tenofovir; TDF; subtypes
12.  Multicenter study of hypoxemia prevalence and quality of oxygen treatment for hospitalized Malawian children 
Although hypoxemic children have high mortality, little is known about hypoxemia prevalence and oxygen administration in African hospitals. We aimed to determine the hypoxemia prevalence and quality of oxygen treatment by local clinicians for hospitalized Malawian children.
The study was conducted in five Malawian hospitals during January–April 2011. We prospectively measured the peripheral oxygen saturation (SpO2) using pulse oximetry for all children <15 years old and also determined clinical eligibility for oxygen treatment using WHO criteria for children <5 years old. We determined oxygen treatment quality by Malawian clinicians by comparing their use of WHO criteria for patients <5 years old using two standards: hypoxemia (SpO2 <90%) and the use of WHO criteria by study staff.
Forty of 761 (5.3%) hospitalized children <15 years old had SpO2 <90%. No hospital used pulse oximetry routinely, and only 9 of 40 (22.5%) patients <15 years old with SpO2 <90% were treated with oxygen by hospital staff. Study personnel using WHO criteria for children <5 years old achieved a higher sensitivity (40.0%) and lower specificity (82.7%) than Malawian clinicians (sensitivity 25.7%, specificity 94.1%).
Although hypoxemia is common, the absence of routine pulse oximetry results in most hospitalized, hypoxemic Malawian children not receiving available oxygen treatment.
PMCID: PMC4030433  PMID: 23584373
Pneumonia; Pediatrics; Hypoxemia; Pulse oximetry; Integrated Management of Childhood Illness; Africa
13.  Treatment Outcomes of AIDS-Associated Kaposi's Sarcoma under a Routine Antiretroviral Therapy Program in Lilongwe, Malawi: Bleomycin/Vincristine Compared to Vincristine Monotherapy 
PLoS ONE  2014;9(3):e91020.
Despite Kaposi's sarcoma (KS) being the most prevalent AIDS-associated cancer in resource limited settings, optimal treatment options remain unknown. We assessed whether bleomycin/vincristine compared to vincristine monotherapy was associated with improved treatment outcomes for AIDS-associated KS among patients initiating combination antiretroviral therapy (cART) in Malawi.
All patients initiating cART and chemotherapy for AIDS-related KS were identified from an electronic data system from the HIV Lighthouse Clinic from 2002 to 2011. Treatment responses were compared between patients receiving vincristine monotherapy and vincristine/bleomycin. Binomial regression models were implemented to assess probability of tumor improvement for patients receiving vincristine/bleomycin compared to vincristine monotherapy after a complete cycle of chemotherapy (9–10 months). A chi-squared test was used to compare changes in CD4 count after six months of chemotherapy.
Of 449 patients with AIDS-associated KS on chemotherapy, 94% received vincristine monotherapy and 6% received bleomycin/vincristine. Distribution of treatment outcomes was different: 29% of patients on vincristine experienced tumor improvement compared to 53% of patients on bleomycin/vincristine. Patients receiving bleomycin/vincristine were 2.25 (95% CI: 1.47, 3.44) times as likely to experience tumor improvement as to those on vincristine monotherapy. This value changed little after adjustment for age and baseline CD4 count: 2.46 (95% CI: 1.57, 3.86). Change in CD4 count was similar for patients receiving vincristine monotherapy and bleomycin/vincristine (p = 0.6).
Bleomycin/vincristine for the treatment of AIDS-associated KS was associated with better tumor response compared to vincristine monotherapy without impairing CD4 count recovery. Replication in larger datasets and randomized controlled trials is necessary.
PMCID: PMC3954589  PMID: 24632813
14.  Determinants of Mortality in a Combined Cohort of 501 Patients With HIV-Associated Cryptococcal Meningitis: Implications for Improving Outcomes 
Cerebrospinal fluid fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated cryptococcal meningitis. The identification of factors associated with mortality informs strategies to improve outcomes.
Background. Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes.
Methods. Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality.
Results. Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7–5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0–1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4–11.1), high peripheral white blood cell count (>10 × 109 cells/L; OR, 8.7; 95% CI, 2.5–30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age.
In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART).
Conclusions. CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.
PMCID: PMC3922213  PMID: 24319084
cryptococcal meningitis; Cryptococcus neoformans; HIV; antiretroviral therapy; mortality (determinants)
15.  Prevalence of HIV and Disease Outcomes on the Medical and Surgical Wards at Kamuzu Central Hospital, Lilongwe, Malawi 
Tropical Medicine and Health  2013;41(4):163-170.
Introduction: The World Health Organization (WHO) recommends HIV Counseling and Testing (HCT) in a range of clinical settings. We describe the characteristics of patients diagnosed with HIV on the medical and surgical wards at a tertiary care hospital in Malawi.
Methods: Under the universal opt-out HCT protocol we characterized the number of new HIV/AIDS infections and associated clinical features among hospitalized surgical and medical patients diagnosed during the course of admission.
Results: All 2985 and 3959 medical and surgical patients, respectively, admitted between April 2012 and January 2013 were screened for HCT. 62% and 89% of medical and surgical patients, respectively, had an unknown status on admission and qualified for testing. Of the patients with an unknown status, a new HIV diagnosis was made in 20% and 7% of medical and surgical patients, respectively. Of the newly diagnosed patients with a CD4 count recorded, 91% and 67% of medical and surgical patients, respectively, had a count less than 350, qualifying for ART by Malawi ART guidelines. Newly HIV-diagnosed medical and surgical patients had an inpatient mortality of 20% and 2%, respectively.
Discussion: While newly diagnosed HIV-positive medical patients had high inpatient mortality and higher rates of WHO stage 3 or 4 conditions, surgical patients presented with less advanced HIV, though still meeting ART initiation guidelines. The medical inpatient wards are an obvious choice for implementing voluntary counseling and testing (VCT), but surgical patients present with less advanced disease and starting treatment in this group could result in more years of life gained.
PMCID: PMC3883455  PMID: 24505214
HIV counseling and testing; inpatient; surgery; medicine; sub-Saharan Africa
16.  Early Experience after Developing a Pathology Laboratory in Malawi, with Emphasis on Cancer Diagnoses 
PLoS ONE  2013;8(8):e70361.
Despite increasing cancer burden in Malawi, pathology services are limited. We describe operations during the first 20 months of a new pathology laboratory in Lilongwe, with emphasis on cancer diagnoses.
Methods and Findings
We performed a cross-sectional study of specimens from the Kamuzu Central Hospital pathology laboratory between July 1, 2011 and February 28, 2013. Patient and specimen characteristics, and final diagnoses are summarized. Diagnoses were categorized as malignant, premalignant, infectious, other pathology, normal or benign, or nondiagnostic. Patient characteristics associated with premalignancy and malignancy were assessed using logistic regression. Of 2772 specimens, 2758 (99%) with a recorded final diagnosis were included, drawn from 2639 unique patients. Mean age was 38 years and 63% were female. Of those with documented HIV status, 51% had unknown status, and 36% with known status were infected. Histologic specimens comprised 91% of cases, and cytologic specimens 9%. Malignant diagnoses were most common overall (n = 861, 31%). Among cancers, cervical cancer was most common (n = 117, 14%), followed by lymphoma (n = 91, 11%), esophageal cancer (n = 86, 10%), sarcoma excluding Kaposi sarcoma (n = 75, 9%), and breast cancer (n = 61, 7%). HIV status was known for 95 (11%) of malignancies, with HIV prevalence ranging from 9% for breast cancer to 81% for cervical cancer. Increasing age was consistently associated with malignancy [bivariable odds ratio 1.24 per decade increase (95% CI 1.19–1.29) among 2685 patients with known age; multivariable odds ratio 1.33 per decade increase (95% CI 1.14–1.56) among 317 patients with known age, gender, and HIV status], while HIV infection and gender were not.
Despite selection and referral bias inherent in these data, a new pathology laboratory in Lilongwe has created a robust platform for cancer care and research. Strategies to effectively capture clinical information for pathologically confirmed cancers can allow these data to complement population-based registration.
PMCID: PMC3737192  PMID: 23950924
17.  Superior Uptake and Outcomes of Early Infant Diagnosis of HIV Services at an Immunization Clinic Versus an “Under-Five” General Pediatric Clinic in Malawi 
Although the Malawian government recommends HIV-exposed infants receive early infant diagnosis of HIV (EID) at “under-five” pediatric clinics (U5Cs), most never enroll. Therefore, we evaluated the integration of EID testing into an immunization clinic (IC) compared to the current standard of EID testing at an U5C.
Prospective observational study.
Using routine provider initiated HIV testing and counseling (PITC) registers, we prospectively studied 1757 children offered PITC at a government IC and U5C. Infants tested by HIV DNA polymerase chain reaction (PCR) were followed until PCR result disclosure or defaulting.
We sampled 877 and 880 consecutive PITC recipients at U5C and IC, respectively. Overall, a 7 fold greater proportion received PITC at IC (84.2% vs 11.4%, p<0.001). PITC recipients at IC were more than 14 months younger (2.6 vs 17.0, p<0.001), with greater proportions HIV-exposed (17.6% vs 5.3%, p<0.001) and PCR eligible (7.9% vs 3.5%, p<0.001).
A higher percentage of IC infants accepted PCR testing (100.0% vs 90.3%, p=0.03). Additionally, IC PCR recipients were 2.5 months younger (3.1 vs 5.6, p<0.001) with 4 times less testing PCR positive (7.1% vs 32.1%, p<0.001). Importantly, a more than 3 fold greater proportion of HIV-exposed infants at IC returned for their PCR result and enrolled into care (78.6% vs 25.0%, p<0.001).
Compared to an U5C, integrating EID testing into an IC is more acceptable, more feasible, enrolls more infants into EID at younger ages, and would likely strengthen Malawi's EID services if expanded.
PMCID: PMC3412370  PMID: 22614897
Africa; pediatrics; prevention of mother-to-child transmission; early infant diagnosis of HIV; HIV DNA PCR; provider initiated HIV testing and counseling
18.  Low Rates of Mother-to-Child HIV Transmission in a Routine Programmatic Setting in Lilongwe, Malawi 
PLoS ONE  2013;8(5):e64979.
The Tingathe program utilizes community health workers to improve prevention of mother-to-child transmission (PMTCT) service delivery. We evaluated the impact of antiretroviral (ARV) regimen and maternal CD4+ count on HIV transmission within the Tingathe program in Lilongwe, Malawi.
We reviewed clinical records of 1088 mother-infant pairs enrolled from March 2009 to March 2011 who completed follow-up to first DNA PCR. Eligibility for antiretroviral treatment (ART) was determined by CD4+ cell count (CD4+) for women not yet on ART. ART-eligible women initiated stavudine-lamivudine-nevirapine. Early ART was defined as ART for ≥14 weeks prior to delivery. For women ineligible for ART, optimal ARV prophylaxis was maternal AZT ≥6 weeks+sdNVP, and infant sdNVP+AZT for 1 week. HIV transmission rates were determined for ARV regimens, and factors associated with vertical transmission were identified using bivariate logistic regression.
Transmission rate at first PCR was 4.1%. Pairs receiving suboptimal ARV prophylaxis were more likely to transmit HIV (10.3%, 95% CI, 5.5–18.1%). ART was associated with reduced transmission (1.4%, 95% CI, 0.6–3.0%), with early ART associated with decreased transmission (no transmission), compared to all other treatment groups (p = 0.001). No association was detected between transmission and CD4+ categories (p = 0.337), trimester of pregnancy at enrollment (p = 0.100), or maternal age (p = 0.164).
Low rates of MTCT of HIV are possible in resource-constrained settings under routine programmatic conditions. No transmissions were observed among women on ART for more than 14 weeks prior to delivery.
PMCID: PMC3669205  PMID: 23741437
19.  Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial 
Lancet  2012;379(9835):2449-2458.
In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks.
The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per μL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with, number NCT00164736.
676 mother–infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5–9) than in the maternal-antiretroviral (4%, 3–6; p=0·0273) or the infant-nevirapine (4%, 2–5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29–48 weeks than during the intervention phase (1·1 [95% CI 1·0–1·2] vs 0·7 [0·7–0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group).
In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity
US Centers for Disease Control and Prevention.
PMCID: PMC3661206  PMID: 22541418
20.  Prevalence of hepatitis C virus infection among human immunodeficiency virus-1-infected pregnant women in Malawi: The BAN study☆ 
In Sub-Saharan Africa, prevalence estimates of hepatitis C virus (HCV) vary widely.
To assess the prevalence of HCV infection among HIV-infected, pregnant women screened for a large clinical trial in Lilongwe, Malawi.
Study design
Plasma from 2041 HIV-infected, pregnant women was screened for anti-HCV IgG using a chemiluminiscent immunometric assay (CIA). Specimens with a signal-cut-off ratio ≥ 1.00 were considered reactive and those with S/Co ratio < 1.00 non-reactive. All CIA-reactive specimens were tested by a recombinant immunoblot assay (RIBA) for anti-HCV and by PCR for HCV RNA.
Of 2041 specimens, 110 (5.3%, 95% CI: 4.5–6.5%) were CIA reactive. Of the 109 CIA reactive specimens available for RIBA testing, 2 (1.8%) were positive, 28 (25.7%) were indeterminate, and 79 (72.5%) were negative. All CIA-reactive specimens were HCV RNA negative (n = 110). The estimated HCV prevalence based on the screening assay alone was 5.3%; based on supplemental RIBA testing, the status of HCV infection remained indeterminate in 1.4% (28/2040, 95% CI: 0.1–2.0) and the prevalence of confirmed HCV infections was 0.1% (2/2040, 95% CI: 0–0.4%).
HCV seroprevalence among HIV-infected, pregnant women in Malawi confirmed by supplemental RIBA HCV 3.0 is low (0.1%); CIA showed a high false-reactivity rate in this population.
PMCID: PMC3652577  PMID: 22658797
HIV; HCV; Pregnant women; Malawi
21.  Quality of Life Among Individuals with HIV Starting Antiretroviral Therapy in Diverse Resource-Limited Areas of the World 
AIDS and Behavior  2012;16(2):266-277.
As Antiretroviral Therapy (ART) is scaled up in low- and middle-income countries, it is important to understand Quality of Life (QOL) correlates including disease severity and person characteristics and to determine the extent of between-country differences among those with HIV. QOL and medical data were collected from 1,563 of the 1,571 participants at entry into a randomized clinical trial of ART conducted in the U.S. (n = 203) and 8 resource-limited countries (n = 1,360) in the Caribbean, South America, Asia, and Africa. Participants were interviewed prior to initiation of ART using a modified version of the ACTG SF-21, a health-related QOL measure including 8 subscales: general health perception, physical functioning, role functioning, social functioning, cognitive functioning, pain, mental health, and energy/fatigue. Other measures included demographics, CD4+ lymphocyte count, plasma HIV-1 RNA viral load. Higher quality of life in each of the 8 QOL subscales was associated with higher CD4+ lymphocyte category. General health perception, physical functioning, role functioning, and energy/fatigue varied by plasma HIV-1 RNA viral load categories. Each QOL subscale included significant variation by country. Only the social functioning subscale varied by sex, with men having greater impairments than women, and only the physical functioning subscale varied by age category. This was the first large-scale international ART trial to conduct a standardized assessment of QOL in diverse international settings, thus demonstrating that implementation of the behavioral assessment was feasible. QOL indicators at study entry varied with disease severity, demographics, and country. The relationship of these measures to treatment outcomes can and should be examined in clinical trials of ART in resource-limited settings using similar methodologies.
PMCID: PMC3182285  PMID: 21499794
Quality of life (QOL); Highly active antiretroviral therapy (HAART); HIV
22.  Practices to improve identification of Adult Antiretroviral Therapy failure at the Lighthouse Trust clinic in Lilongwe, Malawi 
Evaluating treatment failure is critical when deciding to modify antiretroviral therapy (ART). Virologic Assessment Forms (VAFs) were implemented in July 2008 as a prerequisite for ordering viral load. The form requires assessment of clinical and immunologic status.
Using the Electronic Medical Record (EMR), we retrospectively evaluated patients who met 2006 WHO guidelines for immunologic failure (≥15 years old; on ART ≥6 months; CD4 count 50% drop from peak OR CD4 persistently <100 cells) at the Lighthouse Trust clinic from 12/2007–12/2009. We compared virologic screening, VAF implementation and ART modification during the same period using Fisher’s exact tests and unpaired t-tests as appropriate.
Of 7,000 enrolled ART patients ≥ 15 years old with at least two CD4 counts, 10% had immunologic failure with a median follow-up time on ART of 1.4 years (IQR: 0.8–2.3). Forty (6%) viral loads were ordered: 14 (35%) were detectable (>400 HIV RNA copies/mL) and 1 (7%) patient was switched to second-line therapy. Overall, 259 VAFs were completed: 67% for immunologic failure and 33% for WHO Stage 4 condition. Before VAF implementation, 1% of patients had viral loads drawn during routine care, whereas afterwards, 8% did (p<0.0001; 95% CI 0.03–0.08).
Clinicians did not identify a large proportion of immunologic failure patients for screening. Implementation of VAFs produced little improvement in virologic screening during routine care. Better training and monitoring systems are needed.
PMCID: PMC3294101  PMID: 22039960
antiretroviral therapy; treatment failure; second-line therapy; immunologic and virologic screening; capacity building
23.  Analysis of Genetic Linkage of HIV From Couples Enrolled in the HIV Prevention Trials Network 052 Trial 
The Journal of Infectious Diseases  2011;204(12):1918-1926.
Background. The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early initiation of antiretroviral therapy (ART) reduces human immunodeficiency virus (HIV) transmission from HIV-infected adults (index participants) to their HIV-uninfected sexual partners. We analyzed HIV from 38 index-partner pairs and 80 unrelated index participants (controls) to assess the linkage of seroconversion events.
Methods. Linkage was assessed using phylogenetic analysis of HIV pol sequences and Bayesian analysis of genetic distances between pol sequences from index-partner pairs and controls. Selected samples were also analyzed using next-generation sequencing (env region).
Results. In 29 of the 38 (76.3%) cases analyzed, the index was the likely source of the partner’s HIV infection (linked). In 7 cases (18.4%), the partner was most likely infected from a source other than the index participant (unlinked). In 2 cases (5.3%), linkage status could not be definitively established.
Conclusions. Nearly one-fifth of the seroconversion events in HPTN 052 were unlinked. The association of early ART and reduced HIV transmission was stronger when the analysis included only linked events. This underscores the importance of assessing the genetic linkage of HIV seroconversion events in HIV prevention studies involving serodiscordant couples.
PMCID: PMC3209811  PMID: 21990420
24.  Exploration of CYP450 and drug transporter genotypes and correlations with nevirapine exposure in Malawians 
Pharmacogenomics  2011;13(1):113-121.
Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians.
Materials & methods
CYP450 2B6, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects.
Allele frequencies (variant) were: CYP2B6 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*1B (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP2B6 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27–2.40) for area under the concentration time curve (AUC)0–12 h, 1.58 (1.03–2.42) for C0, and 0.53 (0.31–0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP2B6 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027).
Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP2B6 516 was significantly associated with nevirapine exposure.
PMCID: PMC3292264  PMID: 22111602
CYP2B6; CYP450; Malawi; nevirapine; nuclear receptor; P-glycoprotein; pharmacokinetics
25.  Lopinavir/ritonavir Monotherapy After Virologic Failure of First-line Antiretroviral Therapy in Resource-limited Settings 
AIDS (London, England)  2012;26(11):1345-1354.
To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLS).
Open-label pilot study of LPV/r monotherapy in participants on first-line non-nucleoside reverse transcriptase inhibitor 3-drug combination ART with plasma HIV-1 RNA 1000–200 000 copies/mL.
Participants were recruited from 5 sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure (VF) at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r.
Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without VF at 24 weeks (87%). Archived samples with HIV-1 RNA levels < 400 at week 24 (n = 102) underwent ultrasensitive assay. Of these subjects, 62 had levels < 40 copies/mL and 30 had levels 40–200. Fifteen subjects experienced VF, among whom 11 had resistance assessed, and 2 had emergent protease inhibitor mutations. The presence of baseline thymidine analogue mutations and K65R predicted a lower VF rate. Thirteen subjects with VF added FTC/TDF, and 1 subject added FTC/ TDF without VF. At study week 48, 11/14 adding FTC/TDF had HIV-1 RNA levels < 400 copies/mL.
In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity.
PMCID: PMC3443745  PMID: 22441252

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